Trial Outcomes & Findings for A Drug Drug Interaction (DDI) Study of Pirtobrutinib (LOXO-305) and Different Formulations of Midazolam in Healthy Participants (NCT NCT06180967)
NCT ID: NCT06180967
Last Updated: 2025-02-24
Results Overview
PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
15 participants
Primary outcome timeframe
Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Results posted on
2025-02-24
Participant Flow
The study consisted of 2 periods: Period 1 and Period 2. A total of 15 healthy participants were enrolled in the study.
Participant milestones
| Measure |
Period 1: All Participants: Midazolam (IV + Oral Dose)
* Day 1: Participants received a single intravenous (IV) bolus dose of midazolam 250 micrograms (mcg) solution on Day 1.
* Day 3: Participants received a single oral dose of midazolam 500 mcg syrup on Day 3.
A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 1 and Day 3 was observed.
|
Period 2: All Participants: Pirtobrutinib + Midazolam (IV + Oral Dose)
* Day 5-17: Participants received Pirtobrutinib 200 mg tablets orally once daily (QD) in the morning from Day 5 through Day 17;
* Day 15: Participants received single IV bolus dose of Midazolam 250 mcg followed by Pirtobrutinib intake on Day 15.
* Day 17: Participants received a single oral dose of midazolam 500 mcg syrup followed by Pirtobrutinib intake on Day 17.
A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 15 and Day 17 was observed.
|
|---|---|---|
|
Period 1: Day 1 to Day 4
STARTED
|
15
|
0
|
|
Period 1: Day 1 to Day 4
Received at Least 1 Dose of Study Drug
|
15
|
0
|
|
Period 1: Day 1 to Day 4
COMPLETED
|
15
|
0
|
|
Period 1: Day 1 to Day 4
NOT COMPLETED
|
0
|
0
|
|
Period 2: Day 5 to Day 20
STARTED
|
0
|
15
|
|
Period 2: Day 5 to Day 20
Received at Least 1 Dose of Study Drug
|
0
|
15
|
|
Period 2: Day 5 to Day 20
COMPLETED
|
0
|
15
|
|
Period 2: Day 5 to Day 20
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
A Drug Drug Interaction (DDI) Study of Pirtobrutinib (LOXO-305) and Different Formulations of Midazolam in Healthy Participants
Baseline characteristics by cohort
| Measure |
All Participants: Midazolam (IV + Oral Dose) + Pirtobrutinib
n=15 Participants
All participants in the study who received:
* Period 1, Day 1: Participants received a single intravenous (IV) bolus dose of midazolam 250 micrograms (mcg) solution on Day 1.
* Period 1 Day 3: Participants received a single oral dose of midazolam 500 mcg syrup on Day 3. A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 1 and Day 3 was observed.
* Period 2, Day 5-17: Participants received Pirtobrutinib 200 mg tablets orally once daily (QD) in the morning from Day 5 through Day 17
* Period 2, Day 15: Participants received single IV bolus dose of Midazolam 250 mcg followed by Pirtobrutinib intake on Day 15.
* Period 2, Day 17: Participants received a single oral dose of midazolam 500 mcg syrup followed by Pirtobrutinib intake on Day 17. A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 15 and Day 17 was observed.
|
|---|---|
|
Age, Continuous
|
33.9 years
STANDARD_DEVIATION 9.50 • n=5 Participants
|
|
Sex: Female, Male
Female
|
3 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
12 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
7 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
8 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
3 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
10 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
1 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
15 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration
Midazolam
|
4.81 Hours*nanograms per milliliter (h*ng/mL)
Geometric Coefficient of Variation 40.8
|
8.30 Hours*nanograms per milliliter (h*ng/mL)
Geometric Coefficient of Variation 43.2
|
—
|
—
|
|
Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration
Metabolite: 1-OH-medazolam
|
2.24 Hours*nanograms per milliliter (h*ng/mL)
Geometric Coefficient of Variation 41.9
|
2.52 Hours*nanograms per milliliter (h*ng/mL)
Geometric Coefficient of Variation 40.6
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: AUC(0-inf) of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Midazolam
|
5.31 h*ng/mL
Geometric Coefficient of Variation 43.1
|
9.01 h*ng/mL
Geometric Coefficient of Variation 44.0
|
—
|
—
|
|
PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Metabolite: 1-OH-midazolam
|
2.60 h*ng/mL
Geometric Coefficient of Variation 39.9
|
2.92 h*ng/mL
Geometric Coefficient of Variation 42.2
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Midazolam
|
8.84 percentage of AUC0-inf
Geometric Coefficient of Variation 33.7
|
7.42 percentage of AUC0-inf
Geometric Coefficient of Variation 35.3
|
—
|
—
|
|
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Metabolite: 1-OH-midazolam
|
12.9 percentage of AUC0-inf
Geometric Coefficient of Variation 37.5
|
12.2 percentage of AUC0-inf
Geometric Coefficient of Variation 48.6
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: Cmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
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PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Midazolam
|
2.33 nanograms per milliliter (ng/mL)
Geometric Coefficient of Variation 36.7
|
3.68 nanograms per milliliter (ng/mL)
Geometric Coefficient of Variation 34.3
|
—
|
—
|
|
PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Metabolite: 1-OH-midazolam
|
1.25 nanograms per milliliter (ng/mL)
Geometric Coefficient of Variation 42.2
|
1.41 nanograms per milliliter (ng/mL)
Geometric Coefficient of Variation 40.2
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: tmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
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PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Midazolam
|
0.750 Hours
Interval 0.5 to 1.0
|
0.500 Hours
Interval 0.5 to 0.75
|
—
|
—
|
|
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Metabolite: 1-OH-midazolam
|
0.750 Hours
Interval 0.5 to 1.0
|
0.500 Hours
Interval 0.5 to 1.0
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: λz of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
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PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Midazolam
|
0.316 one per hour (1/h)
Geometric Coefficient of Variation 50.7
|
0.227 one per hour (1/h)
Geometric Coefficient of Variation 50.2
|
—
|
—
|
|
PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Metabolite: 1-OH-midazolam
|
0.441 one per hour (1/h)
Geometric Coefficient of Variation 35.4
|
0.419 one per hour (1/h)
Geometric Coefficient of Variation 61.2
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: CL/F of midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration
|
94.2 Liters per hour (L/h)
Geometric Coefficient of Variation 43.1
|
55.5 Liters per hour (L/h)
Geometric Coefficient of Variation 44.0
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: Vz/F of midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration
|
298 Liters
Geometric Coefficient of Variation 29.7
|
244 Liters
Geometric Coefficient of Variation 29.6
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: t½ of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Midazolam
|
2.20 hours
Geometric Coefficient of Variation 50.7
|
3.05 hours
Geometric Coefficient of Variation 50.2
|
—
|
—
|
|
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
Metabolite: 1-OH-midazolam
|
1.57 hours
Geometric Coefficient of Variation 35.4
|
1.65 hours
Geometric Coefficient of Variation 61.2
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: CL of midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration
|
26.0 L/h
Geometric Coefficient of Variation 21.4
|
23.1 L/h
Geometric Coefficient of Variation 26.5
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: Vz of midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration
|
113 Liters
Geometric Coefficient of Variation 34.2
|
105 Liters
Geometric Coefficient of Variation 37.8
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: Vss of midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration
|
78.2 Liters
Geometric Coefficient of Variation 29.4
|
76.1 Liters
Geometric Coefficient of Variation 31.0
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Midazolam
|
8.89 h*ng/mL
Geometric Coefficient of Variation 21.6
|
10.1 h*ng/mL
Geometric Coefficient of Variation 25.1
|
—
|
—
|
|
PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Metabolite: 1-OH-medazolam
|
1.39 h*ng/mL
Geometric Coefficient of Variation 41.7
|
1.21 h*ng/mL
Geometric Coefficient of Variation 35.7
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. Here, 'Number analyzed' signifies participants with available data for each specified category.
PK: AUC0-inf of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Midazolam
|
9.62 h*ng/mL
Geometric Coefficient of Variation 21.4
|
10.8 h*ng/mL
Geometric Coefficient of Variation 26.5
|
—
|
—
|
|
PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Metabolite: 1-OH-medazolam
|
2.13 h*ng/mL
Geometric Coefficient of Variation 43.0
|
1.62 h*ng/mL
Geometric Coefficient of Variation 25.2
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. Here, 'Number analyzed' signifies participants with available data for each specified category.
PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Midazolam
|
7.13 percentage of AUC0-inf
Geometric Coefficient of Variation 37.1
|
6.44 percentage of AUC0-inf
Geometric Coefficient of Variation 42.0
|
—
|
—
|
|
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Metabolite: 1-OH-medazolam
|
19.6 percentage of AUC0-inf
Geometric Coefficient of Variation 24.7
|
24.7 percentage of AUC0-inf
Geometric Coefficient of Variation 11.5
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: Cmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Midazolam
|
6.96 ng/mL
Geometric Coefficient of Variation 34.8
|
6.91 ng/mL
Geometric Coefficient of Variation 27.8
|
—
|
—
|
|
PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Metabolite: 1-OH-medazolam
|
0.512 ng/mL
Geometric Coefficient of Variation 31.7
|
0.475 ng/mL
Geometric Coefficient of Variation 28.6
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: tmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Midazolam
|
0.0833 hours
Interval 0.0833 to 0.25
|
0.0833 hours
Interval 0.0833 to 0.0833
|
—
|
—
|
|
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Metabolite: 1-OH-medazolam
|
0.750 hours
Interval 0.5 to 1.0
|
0.750 hours
Interval 0.5 to 1.0
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: λz of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Midazolam
|
0.229 1/h
Geometric Coefficient of Variation 37.0
|
0.221 1/h
Geometric Coefficient of Variation 49.5
|
—
|
—
|
|
PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Metabolite: 1-OH-medazolam
|
0.224 1/h
Geometric Coefficient of Variation 55.7
|
0.282 1/h
Geometric Coefficient of Variation 47.8
|
—
|
—
|
PRIMARY outcome
Timeframe: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: t1/2 of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Midazolam
|
3.02 hours
Geometric Coefficient of Variation 37.0
|
3.13 hours
Geometric Coefficient of Variation 49.5
|
—
|
—
|
|
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
Metabolite: 1-OH-medazolam
|
3.09 hours
Geometric Coefficient of Variation 55.7
|
2.46 hours
Geometric Coefficient of Variation 47.8
|
—
|
—
|
SECONDARY outcome
Timeframe: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: AUC0-t of Pirtobrutinib was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib
|
54800 h*ng/mL
Geometric Coefficient of Variation 20.0
|
114000 h*ng/mL
Geometric Coefficient of Variation 26.0
|
115000 h*ng/mL
Geometric Coefficient of Variation 25.0
|
211000 h*ng/mL
Geometric Coefficient of Variation 33.8
|
SECONDARY outcome
Timeframe: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: AUCtau of Pirtobrutinib was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib
|
55000 h*ng/mL
Geometric Coefficient of Variation 20.0
|
114000 h*ng/mL
Geometric Coefficient of Variation 26.1
|
116000 h*ng/mL
Geometric Coefficient of Variation 25.0
|
118000 h*ng/mL
Geometric Coefficient of Variation 25.5
|
SECONDARY outcome
Timeframe: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: Cmax of Pirtobrutinib was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib
|
4880 ng/mL
Geometric Coefficient of Variation 18.5
|
8120 ng/mL
Geometric Coefficient of Variation 27.1
|
8620 ng/mL
Geometric Coefficient of Variation 23.1
|
8750 ng/mL
Geometric Coefficient of Variation 27.2
|
SECONDARY outcome
Timeframe: Period 2: 24-hour post-dose on Day 14, Day 15, and Day 17Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: Ctrough of Pirtobrutinib before multiple oral doses administration was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib
|
3060 ng/mL
Geometric Coefficient of Variation 32.1
|
3180 ng/mL
Geometric Coefficient of Variation 36.4
|
3050 ng/mL
Geometric Coefficient of Variation 32.7
|
—
|
SECONDARY outcome
Timeframe: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: tmax of Pirtobrutinib was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib
|
2.50 hours
Interval 1.0 to 4.0
|
3.00 hours
Interval 2.0 to 4.0
|
3.00 hours
Interval 0.75 to 6.0
|
3.00 hours
Interval 1.0 to 4.0
|
SECONDARY outcome
Timeframe: Period 2: Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
PK: CL,ss/F of Pirtobrutinib was reported.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
n=15 Participants
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib
|
1.75 L/h
Geometric Coefficient of Variation 26.1
|
1.72 L/h
Geometric Coefficient of Variation 25.0
|
1.69 L/h
Geometric Coefficient of Variation 25.5
|
—
|
SECONDARY outcome
Timeframe: Period 2: Day 5 and Day 14 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose)Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
RAUC was ratio of Day 14 AUCtau to Day 5 AUCtau.
Outcome measures
| Measure |
Period 1: Oral Midazolam 500 mcg (Day 3)
n=15 Participants
Participants who received a single oral dose of midazolam 500 mcg syrup on Day 3.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15)
Participants who received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17)
Participants who received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|
|
PK: Accumulation Ratio (RAUC) of Pirtobrutinib
|
2.08 Ratio
Geometric Coefficient of Variation 15.9
|
—
|
—
|
—
|
Adverse Events
Period 1: IV Midazolam 250 mcg
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Period 1: Oral Midazolam 500 mcg
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Period 2: Pirtobrutinib 200 mg
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Period 1: IV Midazolam 250 mcg
n=15 participants at risk
Participants received a single IV bolus dose of midazolam 250 mcg solution on Day 1.
|
Period 1: Oral Midazolam 500 mcg
n=15 participants at risk
Participants received a single oral dose of midazolam 500 mcg syrup on Day 3
|
Period 2: Pirtobrutinib 200 mg
n=15 participants at risk
Participants received pirtobrutinib 200 mg tablets orally QD from Day 5 through Day 17.
|
Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg
n=15 participants at risk
Participants received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15.
|
Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg
n=15 participants at risk
Participants received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17.
|
|---|---|---|---|---|---|
|
Gastrointestinal disorders
Constipation
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
6.7%
1/15 • Number of events 1 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
|
Gastrointestinal disorders
Flatulence
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
6.7%
1/15 • Number of events 1 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
|
General disorders
Injection site pain
|
6.7%
1/15 • Number of events 1 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
6.7%
1/15 • Number of events 1 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
|
Renal and urinary disorders
Pollakiuria
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
6.7%
1/15 • Number of events 1 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
|
Respiratory, thoracic and mediastinal disorders
Nasal congestion
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
6.7%
1/15 • Number of events 1 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
6.7%
1/15 • Number of events 1 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
0.00%
0/15 • From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60