Trial Outcomes & Findings for Study to Evaluate Effect of Belatacept on Pharmacokinetics of Inje Cocktail in Healthy Volunteers (NCT NCT01766050)
NCT ID: NCT01766050
Last Updated: 2014-06-27
Results Overview
Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Cmax measured in nanograms per milliliter (ng/mL). Inje cocktail components (Midazolam) measured using High Performance Liquid Chromatography (HPLC) with Tandem Mass Spectrometry (MS/MS) Detection.
COMPLETED
PHASE4
45 participants
Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11
2014-06-27
Participant Flow
Study initiated January 2013 and completed April 2013. Participants (healthy volunteers) checked into a clinical pharmacology unit (CPU) on Day -1 for screening.
45 were enrolled and 22 dosed with study drug. Reasons for not dosing: 5 withdrew consent, 1 lost to follow up, 1 poor/non-compliance, 15 no longer met study criteria, and 1 other.
Participant milestones
| Measure |
Inje Cocktail Alone and Inje Cocktail Plus Belatacept
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
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|---|---|
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Overall Study
STARTED
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22
|
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Overall Study
COMPLETED
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18
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Overall Study
NOT COMPLETED
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4
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Reasons for withdrawal
| Measure |
Inje Cocktail Alone and Inje Cocktail Plus Belatacept
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
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|---|---|
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Overall Study
Adverse Event
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1
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Overall Study
Lost to Follow-up
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1
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Overall Study
Withdrawal by Subject
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2
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Baseline Characteristics
Study to Evaluate Effect of Belatacept on Pharmacokinetics of Inje Cocktail in Healthy Volunteers
Baseline characteristics by cohort
| Measure |
Inje Cocktail Alone and Inje Cocktail Plus Belatacept
n=22 Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
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|---|---|
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Age, Continuous
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31.5 years
STANDARD_DEVIATION 5.96 • n=5 Participants
|
|
Sex: Female, Male
Female
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1 Participants
n=5 Participants
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Sex: Female, Male
Male
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21 Participants
n=5 Participants
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|
Race (NIH/OMB)
American Indian or Alaska Native
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0 Participants
n=5 Participants
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|
Race (NIH/OMB)
Asian
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0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
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0 Participants
n=5 Participants
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|
Race (NIH/OMB)
Black or African American
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7 Participants
n=5 Participants
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Race (NIH/OMB)
White
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15 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
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0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
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0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
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22 participants
n=5 Participants
|
|
Body Mass Index (kg/m^2)
|
24.62 kg/m^2
STANDARD_DEVIATION 2.886 • n=5 Participants
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PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Participants who received any study drug and had at least 1 adequate Pharmacokinetic (PK) profile for any Inje cocktail analytes (parent or metabolite).
Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Cmax measured in nanograms per milliliter (ng/mL). Inje cocktail components (Midazolam) measured using High Performance Liquid Chromatography (HPLC) with Tandem Mass Spectrometry (MS/MS) Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
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|---|---|---|---|---|---|
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Adjusted Geometric Mean Maximum Drug Concentration (Cmax) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
|
24.376 ng/mL
90% Confidence Interval 42 • Interval 21.117 to 28.137
|
24.152 ng/mL
Interval 20.632 to 28.271
|
22.211 ng/mL
Interval 19.131 to 25.787
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24.220 ng/mL
Interval 20.835 to 28.154
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
AUC(0-T): area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration and AUC (INF): AUC from time zero extrapolated to infinite time were measured in ng\*h/mL. Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Midazolam measured using HPLC with MS/MS Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
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|---|---|---|---|---|---|
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Adjusted Geometric Mean Area Under the Concentration Time Curve (AUC) From Zero to Last Concentration (0-T) and AUC Extrapolated to Infinity (INF) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
AUC (0-T);N=22, 21, 21, 20)
|
65.548 ng*h/mL
Interval 53.271 to 80.655
|
68.833 ng*h/mL
Interval 57.008 to 83.111
|
63.303 ng*h/mL
Interval 52.24 to 76.707
|
67.717 ng*h/mL
Interval 56.128 to 81.697
|
—
|
|
Adjusted Geometric Mean Area Under the Concentration Time Curve (AUC) From Zero to Last Concentration (0-T) and AUC Extrapolated to Infinity (INF) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
AUC (INF);N=22, 21, 21, 20)
|
67.743 ng*h/mL
Interval 54.839 to 83.683
|
71.039 ng*h/mL
Interval 58.555 to 86.186
|
65.555 ng*h/mL
Interval 54.019 to 79.554
|
69.841 ng*h/mL
Interval 57.771 to 84.433
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
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|---|---|---|---|---|---|
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Adjusted Geometric Mean Cmax of Losartan With and Without the Coadministration of Belatacept - PK Evaluable Population
|
119.789 ng/mL
Interval 89.629 to 134.485
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118.663 ng/mL
Interval 97.209 to 144.85
|
127.184 ng/mL
Interval 105.467 to 153.373
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126.461 ng/mL
Interval 101.676 to 157.288
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
AUC (0-T): area under the concentration curve from time 0 to the time of the last quantifiable concentration and AUC (INF) extrapolated to infinity were measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
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Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Losartan With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
AUC (0-T) N=22, 21, 21, 20)
|
332.191 ng*h/mL
Interval 283.753 to 388.898
|
336.531 ng*h/mL
Interval 291.278 to 388.815
|
337.487 ng*h/mL
Interval 295.482 to 385.462
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332.400 ng*h/mL
Interval 280.799 to 393.484
|
—
|
|
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Losartan With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
AUC (INF) N=22, 21, 21, 20)
|
338.033 ng*h/mL
Interval 289.143 to 395.189
|
341.644 ng*h/mL
Interval 296.237 to 394.012
|
343.508 ng*h/mL
Interval 301.494 to 391.378
|
338.646 ng*h/mL
Interval 286.824 to 399.831
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Cmax: Maximum observed plasma concentration was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Adjusted Geometric Mean Cmax of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
|
583.047 ng/mL
Interval 473.091 to 718.56
|
734.776 ng/mL
Interval 587.28 to 919.316
|
753.126 ng/mL
Interval 597.946 to 948.579
|
686.929 ng/mL
Interval 555.59 to 849.315
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
AUC(0-T): Area under the plasma concentration-time curve from time zero zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity were measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
AUC (0-T); (N= 22, 21, 21, 20)
|
1361.024 ng*h/mL
Interval 1066.457 to 1736.953
|
1577.017 ng*h/mL
Interval 1200.238 to 2072.075
|
1671.173 ng*h/mL
Interval 1278.936 to 2183.704
|
1653.491 ng*h/mL
Interval 1264.315 to 2162.463
|
—
|
|
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
AUC (INF); (N= 22, 19, 21, 18)
|
1368.593 ng*h/mL
Interval 1072.836 to 1745.885
|
1632.455 ng*h/mL
Interval 1251.956 to 2128.597
|
1679.693 ng*h/mL
Interval 1286.299 to 2193.4
|
1779.717 ng*h/mL
Interval 1380.25 to 2294.798
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Cmax was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Adjusted Geometric Mean Cmax of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population
|
0.927 ng/mL
Interval 0.566 to 1.518
|
0.800 ng/mL
Interval 0.512 to 1.25
|
0.855 ng/mL
Interval 0.553 to 1.32
|
0.794 ng/mL
Interval 0.49 to 1.286
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
AUC(0-T): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity, were measured as ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population
AUC (0-T); N= 21, 19, 19, 19
|
6.176 ng*h/mL
Interval 3.466 to 11.005
|
5.651 ng*h/mL
Interval 3.305 to 9.661
|
6.195 ng*h/mL
Interval 3.705 to 10.358
|
5.949 ng*h/mL
Interval 3.465 to 10.215
|
—
|
|
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population
AUC (INF); N= 18, 17, 18, 15
|
6.220 ng*h/mL
Interval 3.743 to 10.337
|
5.455 ng*h/mL
Interval 3.372 to 8.825
|
6.412 ng*h/mL
Interval 4.2 to 9.79
|
6.359 ng*h/mL
Interval 1.143 to 9.76
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Adjusted Geometric Mean Cmax of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population
|
4696.505 ng/mL
Interval 4252.803 to 5186.499
|
4450.019 ng/mL
Interval 4172.484 to 4746.014
|
4332.326 ng/mL
Interval 3993.257 to 4700.186
|
4479.687 ng/mL
Interval 4141.21 to 4845.83
|
—
|
PRIMARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. AUC (0-T) and AUC (INF) were measured as ng\*h/mL.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population
AUC (0-T); N= 22, 21, 21, 18
|
37394.5 ng*h/mL
Interval 33103.4 to 42241.8
|
35200.3 ng*h/mL
Interval 31255.9 to 39642.5
|
36853.4 ng*h/mL
Interval 32319.8 to 42022.9
|
38407.0 ng*h/mL
Interval 34164.2 to 43176.7
|
—
|
|
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population
AUC (INF); N= 22, 21, 21, 18
|
40084.1 ng*h/mL
Interval 34881.6 to 46062.5
|
37647.8 ng*h/mL
Interval 32705.5 to 43336.9
|
40149.9 ng*h/mL
Interval 34434.3 to 46814.1
|
41537.6 ng*h/mL
Interval 36092.9 to 47803.7
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Tmax was measured in hours (h).
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Midazolam (N=22,21,21,20)
|
0.50 h
Interval 0.5 to 1.5
|
0.50 h
Interval 0.5 to 1.5
|
0.50 h
Interval 0.5 to 1.5
|
1.0 h
Interval 0.5 to 1.03
|
—
|
|
Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Losartan (N= 22, 21, 21, 20)
|
1.52 h
Interval 0.5 to 3.0
|
2.00 h
Interval 0.5 to 4.0
|
1.50 h
Interval 0.5 to 3.0
|
1.50 h
Interval 0.5 to 3.0
|
—
|
|
Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Omeprazole (N=22,21,21,20)
|
2.00 h
Interval 1.5 to 4.0
|
3.00 h
Interval 1.0 to 8.05
|
3.00 h
Interval 1.0 to 5.0
|
3.00 h
Interval 1.0 to 12.0
|
—
|
|
Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Dextromethorphan (N=21, 19, 19, 19)
|
3.00 h
Interval 1.0 to 6.0
|
3.00 h
Interval 1.5 to 6.0
|
3.00 h
Interval 1.5 to 5.15
|
3.00 h
Interval 1.0 to 6.0
|
—
|
|
Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Caffeine (N= 22,21,21,18)
|
1.00 h
Interval 0.5 to 2.0
|
1.00 h
Interval 0.5 to 3.0
|
1.50 h
Interval 0.5 to 4.0
|
1.50 h
Interval 0.5 to 2.0
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. T-HALF was measured in hours (h).
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Caffeine (N=22, 21, 21, 18)
|
5.61 h
Standard Deviation 1.87
|
5.71 h
Standard Deviation 2.01
|
6.17 h
Standard Deviation 2.29
|
6.03 h
Standard Deviation 2.13
|
—
|
|
Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Dextromethorphan (N=18, 17, 18, 15)
|
6.76 h
Standard Deviation 2.09
|
6.98 h
Standard Deviation 2.67
|
6.33 h
Standard Deviation 1.69
|
6.70 h
Standard Deviation 2.29
|
—
|
|
Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Midazolam (N=22, 21, 21, 20)
|
4.01 h
Standard Deviation 1.86
|
4.43 h
Standard Deviation 1.89
|
4.27 h
Standard Deviation 1.88
|
4.05 h
Standard Deviation 1.61
|
—
|
|
Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Losartan (N=22, 21, 21, 20)
|
2.96 h
Standard Deviation 1.29
|
2.56 h
Standard Deviation 1.31
|
3.30 h
Standard Deviation 1.49
|
2.87 h
Standard Deviation 1.52
|
—
|
|
Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Omeprazole (N= 22, 19, 21, 18)
|
1.19 h
Standard Deviation 0.497
|
1.39 h
Standard Deviation 0.569
|
1.28 h
Standard Deviation 0.470
|
1.36 h
Standard Deviation 0.907
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. CLT/F was measured as liters/hour (L/h)
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Midazolam (N=22, 21, 21, 20)
|
73.8 L/h
Geometric Coefficient of Variation 49
|
71.3 L/h
Geometric Coefficient of Variation 48
|
77.3 L/h
Geometric Coefficient of Variation 50
|
71.4 L/h
Geometric Coefficient of Variation 51
|
—
|
|
Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Losartan (N=22, 21, 21, 20)
|
148 L/h
Geometric Coefficient of Variation 37
|
146 L/h
Geometric Coefficient of Variation 36
|
146 L/h
Geometric Coefficient of Variation 34
|
151 L/h
Geometric Coefficient of Variation 44
|
—
|
|
Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Omeprazole (N=22, 19, 21, 18)
|
29.2 L/h
Geometric Coefficient of Variation 66
|
23.7 L/h
Geometric Coefficient of Variation 72
|
24.7 L/h
Geometric Coefficient of Variation 79
|
25.3 L/h
Geometric Coefficient of Variation 69
|
—
|
|
Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Dextromethorphan (N=18,17,18,18)
|
3916 L/h
Geometric Coefficient of Variation 85
|
4247 L/h
Geometric Coefficient of Variation 84
|
4264 L/h
Geometric Coefficient of Variation 126
|
3968 L/h
Geometric Coefficient of Variation 107
|
—
|
|
Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population
Caffeine (N=22, 21, 21, 18)
|
4.99 L/h
Geometric Coefficient of Variation 34
|
5.30 L/h
Geometric Coefficient of Variation 32
|
4.97 L/h
Geometric Coefficient of Variation 36
|
4.83 L/h
Geometric Coefficient of Variation 36
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Samples for assessment of plasma concentrations of Inje cocktail component metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail component metabolites were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
1'-Hydroxy-Midazolam (N=22, 21, 21, 20)
|
11.1 ng/mL
Geometric Coefficient of Variation 40
|
11.9 ng/mL
Geometric Coefficient of Variation 40
|
11.4 ng/mL
Geometric Coefficient of Variation 38
|
12.3 ng/mL
Geometric Coefficient of Variation 36
|
—
|
|
Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
E-3174 (N=22, 21, 21, 20)
|
262 ng/mL
Geometric Coefficient of Variation 37
|
276 ng/mL
Geometric Coefficient of Variation 33
|
300 ng/mL
Geometric Coefficient of Variation 33
|
291 ng/mL
Geometric Coefficient of Variation 41
|
—
|
|
Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
5-Hydroxyomeprazole (N=22, 21, 21, 20)
|
335 ng/mL
Geometric Coefficient of Variation 41
|
360 ng/mL
Geometric Coefficient of Variation 40
|
332 ng/mL
Geometric Coefficient of Variation 38
|
337 ng/mL
Geometric Coefficient of Variation 38
|
—
|
|
Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
Dextrorphan (N=21,20,20,19)
|
342 ng/mL
Geometric Coefficient of Variation 30
|
324 ng/mL
Geometric Coefficient of Variation 32
|
312 ng/mL
Geometric Coefficient of Variation 31
|
331 ng/mL
Geometric Coefficient of Variation 35
|
—
|
|
Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
Paraxanthine (N=17,19,18,18)
|
1291 ng/mL
Geometric Coefficient of Variation 15
|
1367 ng/mL
Geometric Coefficient of Variation 12
|
1320 ng/mL
Geometric Coefficient of Variation 13
|
1358 ng/mL
Geometric Coefficient of Variation 15
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration \[AUC(0-T)\] was measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
1'-hydroxy-midazolam (N=22, 21, 21, 20)
|
28.9 ng*h/mL
Geometric Coefficient of Variation 39
|
31.8 ng*h/mL
Geometric Coefficient of Variation 30
|
32.5 ng*h/mL
Geometric Coefficient of Variation 32
|
33.6 ng*h/mL
Geometric Coefficient of Variation 27
|
—
|
|
AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
E-3174 (N= 22,21,21,20)
|
1995 ng*h/mL
Geometric Coefficient of Variation 32
|
1999 ng*h/mL
Geometric Coefficient of Variation 29
|
2089 ng*h/mL
Geometric Coefficient of Variation 30
|
2072 ng*h/mL
Geometric Coefficient of Variation 37
|
—
|
|
AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
5-hydroxyomeprazole (N=22,21,21,20)
|
997 ng*h/mL
Geometric Coefficient of Variation 36
|
967 ng*h/mL
Geometric Coefficient of Variation 33
|
929 ng*h/mL
Geometric Coefficient of Variation 35
|
995 ng*h/mL
Geometric Coefficient of Variation 35
|
—
|
|
AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
dextrorphan (N=21,20,20,19)
|
1636 ng*h/mL
Geometric Coefficient of Variation 27
|
1570 ng*h/mL
Geometric Coefficient of Variation 26
|
1519 ng*h/mL
Geometric Coefficient of Variation 27
|
1644 ng*h/mL
Geometric Coefficient of Variation 26
|
—
|
|
AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
paraxanthine (N=17,19,18,18)
|
20592 ng*h/mL
Geometric Coefficient of Variation 15
|
21077 ng*h/mL
Geometric Coefficient of Variation 16
|
20680 ng*h/mL
Geometric Coefficient of Variation 18
|
21353 ng*h/mL
Geometric Coefficient of Variation 20
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Area under the plasma concentration-time curve from time zero extrapolated to infinite time \[AUC(INF)\] was measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
1'-hydroxy-midazolam (N=22,21,20,20)
|
30.5 ng*h/mL
Geometric Coefficient of Variation 38
|
33.8 ng*h/mL
Geometric Coefficient of Variation 32
|
32.9 ng*h/mL
Geometric Coefficient of Variation 27
|
35.1 ng*h/mL
Geometric Coefficient of Variation 27
|
—
|
|
AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
E-3174 (N=22,20,21,20)
|
2103 ng*h/mL
Geometric Coefficient of Variation 32
|
2060 ng*h/mL
Geometric Coefficient of Variation 29
|
2187 ng*h/mL
Geometric Coefficient of Variation 31
|
2182 ng*h/mL
Geometric Coefficient of Variation 38
|
—
|
|
AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
5-hydroxyomeprazole (N=22,20,21,17
|
1010 ng*h/mL
Geometric Coefficient of Variation 36
|
990 ng*h/mL
Geometric Coefficient of Variation 34
|
938 ng*h/mL
Geometric Coefficient of Variation 35
|
1063 ng*h/mL
Geometric Coefficient of Variation 32
|
—
|
|
AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
dextrorphan (N=21,20,20,19)
|
1679 ng*h/mL
Geometric Coefficient of Variation 25
|
1610 ng*h/mL
Geometric Coefficient of Variation 25
|
1562 ng*h/mL
Geometric Coefficient of Variation 26
|
1682 ng*h/mL
Geometric Coefficient of Variation 25
|
—
|
|
AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
paraxanthine (N=7,8,6,6)
|
22401 ng*h/mL
Geometric Coefficient of Variation 18
|
22905 ng*h/mL
Geometric Coefficient of Variation 24
|
22063 ng*h/mL
Geometric Coefficient of Variation 12
|
21874 ng*h/mL
Geometric Coefficient of Variation 20
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Time of maximum observed plasma concentration (Tmax) was measured in hours (h).
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
1'-Hydroxy-Midazolam (N=22,21,21,20)
|
1.00 h
Interval 0.5 to 1.5
|
1.00 h
Interval 0.5 to 2.0
|
1.00 h
Interval 0.5 to 1.5
|
1.00 h
Interval 0.5 to 1.5
|
—
|
|
Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
E-3174 (N=22, 21, 21, 20)
|
4.00 h
Interval 3.0 to 5.03
|
4.00 h
Interval 2.0 to 8.0
|
4.00 h
Interval 3.0 to 5.15
|
4.00 h
Interval 3.0 to 6.02
|
—
|
|
Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
5-Hydroxyomeprazole (N=22,21,21,20)
|
2.00 h
Interval 1.5 to 5.0
|
3.00 h
Interval 1.0 to 8.05
|
3.00 h
Interval 1.0 to 5.0
|
2.53 h
Interval 1.0 to 12.0
|
—
|
|
Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
Dextrorphan (N=21,20,20,19)
|
2.00 h
Interval 1.5 to 4.0
|
2.00 h
Interval 1.5 to 4.0
|
2.00 h
Interval 1.5 to 3.0
|
2.00 h
Interval 1.5 to 4.0
|
—
|
|
Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
Paraxanthine (N=17, 19, 18, 18)
|
8.00 h
Interval 3.0 to 12.02
|
8.00 h
Interval 5.0 to 12.0
|
8.00 h
Interval 4.0 to 12.0
|
8.00 h
Interval 4.0 to 12.0
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Plasma half-life (T-HALF) was measured in hours (h). Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
1'-Hydroxy-Midazolam (N=22,21,20,20)
|
5.29 h
Standard Deviation 2.98
|
6.35 h
Standard Deviation 3.60
|
5.61 h
Standard Deviation 3.47
|
5.31 h
Standard Deviation 2.65
|
—
|
|
T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
E-3174 (N=22, 20, 21, 20)
|
4.86 h
Standard Deviation 0.749
|
4.57 h
Standard Deviation 0.757
|
4.75 h
Standard Deviation 0.757
|
4.88 h
Standard Deviation 0.690
|
—
|
|
T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
5-Hydroxyomeprazole (N=22,20,21,17)
|
1.43 h
Standard Deviation 0.308
|
1.55 h
Standard Deviation 0.397
|
1.52 h
Standard Deviation 0.371
|
1.54 h
Standard Deviation 0.624
|
—
|
|
T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
Dextrorphan (N=21,20,20,19)
|
4.26 h
Standard Deviation 1.60
|
4.36 h
Standard Deviation 1.46
|
4.23 h
Standard Deviation 1.13
|
4.08 h
Standard Deviation 0.999
|
—
|
|
T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population
Paraxanthine (N=7,8,6,6)
|
7.33 h
Standard Deviation 1.91
|
6.86 h
Standard Deviation 1.71
|
7.33 h
Standard Deviation 1.55
|
7.44 h
Standard Deviation 2.67
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=17 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of Paraxanthine AUC(0-T) to Caffeine AUC(0-T) and Paraxanthine AUC (INF) to Caffeine AUC (INF), Corrected for Molecular Weight [MR_AUC(0-T) and MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC(0-T) ratio; N=17,19,18,18
|
0.627 ratio
Geometric Coefficient of Variation 24
|
0.677 ratio
Geometric Coefficient of Variation 17
|
0.635 ratio
Geometric Coefficient of Variation 20
|
0.603 ratio
Geometric Coefficient of Variation 21
|
—
|
|
Ratio of Paraxanthine AUC(0-T) to Caffeine AUC(0-T) and Paraxanthine AUC (INF) to Caffeine AUC (INF), Corrected for Molecular Weight [MR_AUC(0-T) and MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC(INF) ratio; N=7, 8, 6, 6
|
0.827 ratio
Geometric Coefficient of Variation 15
|
0.827 ratio
Geometric Coefficient of Variation 8
|
0.799 ratio
Geometric Coefficient of Variation 14
|
0.781 ratio
Geometric Coefficient of Variation 12
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and their metabolites were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=17 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of Paraxanthine (Cmax) to Caffeine (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
|
0.303 ratio
Geometric Coefficient of Variation 22
|
0.337 ratio
Geometric Coefficient of Variation 15
|
0.333 ratio
Geometric Coefficient of Variation 23
|
0.323 ratio
Geometric Coefficient of Variation 20
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of E-3174 AUC(0-T) to Losartan AUC(0-T) and E3174 AUC (INF) to Losartan AUC (INF) Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC (0-T) ratio; N=22,21,21,20
|
5.81 ratio
Geometric Coefficient of Variation 32
|
5.75 ratio
Geometric Coefficient of Variation 33
|
5.99 ratio
Geometric Coefficient of Variation 33
|
6.17 ratio
Geometric Coefficient of Variation 33
|
—
|
|
Ratio of E-3174 AUC(0-T) to Losartan AUC(0-T) and E3174 AUC (INF) to Losartan AUC (INF) Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC (INF) ratio; N=22,20,21,20
|
6.02 ratio
Geometric Coefficient of Variation 30
|
5.99 ratio
Geometric Coefficient of Variation 32
|
6.16 ratio
Geometric Coefficient of Variation 32
|
6.37 ratio
Geometric Coefficient of Variation 31
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of E-3174 (Cmax) to Losartan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
|
2.31 ratio
Geometric Coefficient of Variation 39
|
2.24 ratio
Geometric Coefficient of Variation 45
|
2.26 ratio
Geometric Coefficient of Variation 43
|
2.26 ratio
Geometric Coefficient of Variation 45
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (5-Hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of 5-Hydroxyomeprazole AUC(0-T) to Omeprazole AUC(0-T) and 5-Hydroxyomeprazole AUC(INF) to Omeprazole AUC(INF) , Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC (0-T) ratio; N=22,21,21,20
|
0.700 ratio
Geometric Coefficient of Variation 57
|
0.609 ratio
Geometric Coefficient of Variation 66
|
0.551 ratio
Geometric Coefficient of Variation 70
|
0.610 ratio
Geometric Coefficient of Variation 66
|
—
|
|
Ratio of 5-Hydroxyomeprazole AUC(0-T) to Omeprazole AUC(0-T) and 5-Hydroxyomeprazole AUC(INF) to Omeprazole AUC(INF) , Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC (INF) ratio; N=22,19,21,17
|
0.705 ratio
Geometric Coefficient of Variation 56
|
0.558 ratio
Geometric Coefficient of Variation 61
|
0.553 ratio
Geometric Coefficient of Variation 69
|
0.679 ratio
Geometric Coefficient of Variation 62
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (5-hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of 5-Hydroxyomeprazole (Cmax) to Omeprazole (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
|
0.548 ratio
Geometric Coefficient of Variation 54
|
0.471 ratio
Geometric Coefficient of Variation 60
|
0.424 ratio
Geometric Coefficient of Variation 65
|
0.478 ratio
Geometric Coefficient of Variation 59
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (5-dextrorphan ) to parent (dextromethorphan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of 5-Dextrorphan AUC(0-T) to Dextromethorphan AUC(0-T) and 5-Dextrorphan AUC(INF) to Dextromethorphan AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC (0-T) ratio; N=21,20,20,19
|
201 ratio
Geometric Coefficient of Variation 103
|
200 ratio
Geometric Coefficient of Variation 94
|
177 ratio
Geometric Coefficient of Variation 124
|
193 ratio
Geometric Coefficient of Variation 99
|
—
|
|
Ratio of 5-Dextrorphan AUC(0-T) to Dextromethorphan AUC(0-T) and 5-Dextrorphan AUC(INF) to Dextromethorphan AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC (INF) ratio; N=18,17,18,15
|
173 ratio
Geometric Coefficient of Variation 95
|
177 ratio
Geometric Coefficient of Variation 90
|
170 ratio
Geometric Coefficient of Variation 122
|
173 ratio
Geometric Coefficient of Variation 102
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (5-dextrorphan) to parent (dextromethorphan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=19 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of 5-Dextrorphan (Cmax) to Dextromethorphan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
|
280 ratio
Geometric Coefficient of Variation 107
|
303 ratio
Geometric Coefficient of Variation 99
|
275 ratio
Geometric Coefficient of Variation 88
|
303 ratio
Geometric Coefficient of Variation 84
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of 1'-Hydroxy-Midazolam AUC(0-T) to Midazolam AUC(0-T) and 1'-Hydroxy-Midazolam AUC(INF) to Midazolam AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_AUC (0-T) ratio; N=22, 21, 21, 20
|
0.421 ratio
Geometric Coefficient of Variation 56
|
0.447 ratio
Geometric Coefficient of Variation 46
|
0.495 ratio
Geometric Coefficient of Variation 55
|
0.472 ratio
Geometric Coefficient of Variation 55
|
—
|
|
Ratio of 1'-Hydroxy-Midazolam AUC(0-T) to Midazolam AUC(0-T) and 1'-Hydroxy-Midazolam AUC(INF) to Midazolam AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population
MR_(INF) ratio; N=22, 21, 20, 20
|
0.428 ratio
Geometric Coefficient of Variation 57
|
0.460 ratio
Geometric Coefficient of Variation 47
|
0.479 ratio
Geometric Coefficient of Variation 52
|
0.478 ratio
Geometric Coefficient of Variation 55
|
—
|
SECONDARY outcome
Timeframe: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11Population: Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Ratio of 1'-Hydroxy-Midazolam (Cmax) to Midazolam (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
|
0.432 ratio
Geometric Coefficient of Variation 45
|
0.476 ratio
Geometric Coefficient of Variation 44
|
0.497 ratio
Geometric Coefficient of Variation 46
|
0.490 ratio
Geometric Coefficient of Variation 46
|
—
|
SECONDARY outcome
Timeframe: Day 1 to Day of discharge (Day 46±2)Population: All participants who received any study medication.
Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Events captured from Day 1 (pre-dose) to last day prior to discharge (Day 46 ±2). In the total group, a participant with an AE is only counted once (ie, data reflected in Days 1, 4, 7, and 11 below could be the same participant with an AE on multiple days of the study).
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
n=22 Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants
Adverse Events
|
4 participants
|
2 participants
|
1 participants
|
1 participants
|
5 participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants
SAEs
|
0 participants
|
0 participants
|
0 participants
|
0 participants
|
0 participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants
Deaths
|
0 participants
|
0 participants
|
0 participants
|
0 participants
|
0 participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants
AEs leading to discontinuation
|
0 participants
|
0 participants
|
1 participants
|
0 participants
|
1 participants
|
SECONDARY outcome
Timeframe: Day -1 to Day 46 ±2 days or at early terminationPopulation: Participants who received any study medication and had laboratory test results.
Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46, and at early termination, after 10 hours fasting. Upper limits of normal (ULN); Lower limits of normal (LLN); Pre-therapy (Rx); micromoles per liter (µmol/L); millimoles per liter (mmol/L); grams per liter (g/L); Units per liter (U/L); Aspartate Aminotransferase (AST); Blood Urea Nitrogen (BUN) Total Bilirubin: \>1.1\*ULN if Pre-Rx\<= ULN or Pre-Rx is missing, or \>1.2\*Pre-Rx if Pre-Rx \>ULN. AST: \>1.25\*Pre-Rx if Pre-Rx \>ULN or 1.25\*ULN if Pre-Rx \<= ULN or Pre-Rx is missing. BUN: \>1.1\*ULN if Pre-Rx\<= ULN or Pre-Rx is missing, or \>1.2\*Pre-Rx if Pre-Rx \>ULN. Phosphorus: \<0.85\*LLN if Pre-RX \>= LLN or is missing or if Pre-Rx \< LLN. total Protein: \<0.9\*LLN if Pre-Rx\>= LLN or is missing or Pre-Rx \> LLN. Creatine Kinase: \>1.5\*Pre-Rx if Pre-Rx \> ULN or is missing or Pre-Rx is \<= ULN. Lactate Dehydrogenase: \>1.25\*ULN if Pre-Rx \<= ULN or missing, \>1.5\*Pre-Rx if Pre-Rx \> ULN.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
Total bilirubin >1.1*ULN µmol/L (N=22)
|
1 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
AST >1.25*Pre-Rx U/L (N=22)
|
1 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
BUN >1.1*ULN mmol/L (N=22)
|
1 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
Inorganic Phosphorus <0.85*LLN mmol/L (N=22)
|
1 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
Total Protein <0.9*LLN g/L (N=22)
|
1 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
Creatine Kinase > 1.5* Pre-Rx U/L (N=22)
|
2 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
Lactate Dehydrogenase >1.25*ULN U/L (N=22)
|
1 participants
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Day -1 to Day 46 ±2 days or at early terminationPopulation: Participants who received any study medication and had laboratory test results.
Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46 ±2, and at early termination, after 10 hours fasting. Leukocytes: \*10\^9 cells per liter (c/L) \< 0.85\*Pre-Rx if Pre-Rx \< LLN or \<0.9\*LLN if LLN \<= Pre-Rx or Pre-Rx is missing. Neutrophils (absolute): \*10\^12 c/L \< 0.85\* Pre-Rx if Pre-Rx \< 1.5, \<1.5 if Pre-Rx \>= 1.5, \< 1.5 if Pre-Rx missing. Urine blood from dipstick: \>=2 if Pre-Rx \<1 or was missing or if Pre-Rx \>=1. Urinary microscopic white blood cells (WBC) and red blood cells (RBC) \>= 2 if Pre-Rx \<2 or if Pre-Rx was missing or \>=4 if Pre-Rx \>=2.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants
Leukocytes <0.85*Pre-Rx *10^9 c/L (N=22)
|
1 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants
Neutrophils <0.85*Pre-Rx *10^12 c/L (N=22)
|
4 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants
Urine Blood >= 2 (N=22)
|
2 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants
Urinary RBC microscopic >= 2 (N=8)
|
1 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants
Urinary WBC microscopic >= 2 (N=8)
|
1 participants
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Day 1 to Day 46 ±2 days or at early terminationPopulation: All participants who received any study medication and had an ECG performed on Day 1, Day 46 or early termination.
Participants had 12-Lead electrocardiograms (ECGs) performed at Screening Visit, Day 1 prior to dosing, Day 46 ±2, and at early termination. Definition of out-of-range: PR Interval \>210 milliseconds (msec); QRS \> 120 msec, QT \> 500 msec or \> 30 msec change from baseline (Day 1); QT with Fridericia correction (QTcF) \> 450 msec or change from baseline of \> 30 msec to \<= 60 msec or change from baseline \> 60 msec.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Number of Participants With Out-of-Range Electrocardiogram Intervals - All Treated Participants
Day 46 (N=18)
|
0 participants
|
—
|
—
|
—
|
—
|
|
Number of Participants With Out-of-Range Electrocardiogram Intervals - All Treated Participants
Early Termination (N=2)
|
0 participants
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11Population: All participants who received any study medication and had a baseline and specific day blood pressure measurement available.
Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Pressures were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants
Systolic 0.5 hour post dose (N=22,21,21,20)
|
-0.6 mm Hg
Standard Deviation 10.15
|
0.1 mm Hg
Standard Deviation 12.81
|
-4.9 mm Hg
Standard Deviation 9.05
|
-4.7 mm Hg
Standard Deviation 10.13
|
—
|
|
Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants
Systolic 2.0 hour post dose (N=22,21,21,20)
|
0.2 mm Hg
Standard Deviation 10.09
|
2.0 mm Hg
Standard Deviation 11.79
|
-2.7 mm Hg
Standard Deviation 9.85
|
-2.9 mm Hg
Standard Deviation 11.73
|
—
|
|
Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants
Diastolic 0.5 hour post dose (N=22,21,21,20)
|
-1.7 mm Hg
Standard Deviation 6.52
|
-0.2 mm Hg
Standard Deviation 6.03
|
-2.2 mm Hg
Standard Deviation 7.54
|
-2.2 mm Hg
Standard Deviation 5.38
|
—
|
|
Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants
Diastolic 2.0 hour post dose (N=22,21,21,20)
|
0.9 mm Hg
Standard Deviation 4.67
|
-2.0 mm Hg
Standard Deviation 4.53
|
-3.4 mm Hg
Standard Deviation 5.22
|
-1.0 mm Hg
Standard Deviation 5.83
|
—
|
SECONDARY outcome
Timeframe: Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11Population: All participants who received study medication and had baseline and specific day measurement.
Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and the heart rate was measured in beats per minute (bpm). Heart Rates were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=22 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
n=21 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
n=20 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Mean Change From Baseline in Sitting Heart Rate - All Treated Participants
Heart Rate 0.5 hour post dose (N=22, 21, 21, 20)
|
-3.3 bpm
Standard Deviation 12.38
|
-4.2 bpm
Standard Deviation 13.15
|
-1.8 bpm
Standard Deviation 12.58
|
-1.6 bpm
Standard Deviation 10.03
|
—
|
|
Mean Change From Baseline in Sitting Heart Rate - All Treated Participants
Heart Rate 2.0 hour post dose (N=22, 21, 21, 20)
|
-3.5 bpm
Standard Deviation 10.61
|
0.2 bpm
Standard Deviation 13.86
|
0.5 bpm
Standard Deviation 11.95
|
3.1 bpm
Standard Deviation 11.91
|
—
|
SECONDARY outcome
Timeframe: Baseline and Day 46 ±2 daysPopulation: All participants who had received study drug during the treatment period and had measurements at baseline and at discharge.
Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Systolic and Diastolic blood pressures were taken on Day 46 (day of discharge from the study). Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Study Discharge (Day 46±2 Days)
Systolic (N=18)
|
-5.9 mm Hg
Standard Deviation 11.25
|
—
|
—
|
—
|
—
|
|
Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Study Discharge (Day 46±2 Days)
Diastolic (N=18)
|
-5.7 mm Hg
Standard Deviation 8.87
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Baseline and Day 46 ±2 daysPopulation: All participants who received study drug during the treatment period and had measurements at baseline and discharge.
Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and was measured in beats per minute (bpm). Hear rate was taken on Day 46 (day of discharge) during the follow up period. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Outcome measures
| Measure |
Day 1 Inje Cocktail
n=18 Participants
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1.
|
Day 4 Inje Cocktail Plus Belatacept
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4.
|
Day 7 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7.
|
Day 11 Inje Cocktail
Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11.
|
All Participants
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
|
|---|---|---|---|---|---|
|
Mean Change From Baseline in Heart Rate at Study Discharge (Day 46±2 Days)
|
1.0 bpm
Standard Deviation 15.86
|
—
|
—
|
—
|
—
|
Adverse Events
Inje Cocktail Alone and Inje Cocktail Plus Belatacept
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Inje Cocktail Alone and Inje Cocktail Plus Belatacept
n=22 participants at risk
Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.
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Nervous system disorders
Headache
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13.6%
3/22 • Day 1 to Day of discharge (Day 46 ±2 days)
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
- Publication restrictions are in place
Restriction type: OTHER