Trial Outcomes & Findings for Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Health Volunteers (NCT NCT03864406)
NCT ID: NCT03864406
Last Updated: 2023-12-01
Results Overview
Area under the concentration versus time curve from 0 to infinity (AUC0-∞) following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 to measure the total drug exposure was analyzed by the linear up/log down trapezoidal rule using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA).
COMPLETED
PHASE1
12 participants
Total drug exposure at time point zero to infinity on days 1, 7, & 13
2023-12-01
Participant Flow
Participant milestones
| Measure |
Pharmacokinetic Study in Healthy Volunteers
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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|---|---|
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Overall Study
STARTED
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12
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Overall Study
COMPLETED
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12
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Overall Study
NOT COMPLETED
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0
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Health Volunteers
Baseline characteristics by cohort
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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|---|---|
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Age, Categorical
<=18 years
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0 Participants
n=5 Participants
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Age, Categorical
Between 18 and 65 years
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12 Participants
n=5 Participants
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Age, Categorical
>=65 years
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0 Participants
n=5 Participants
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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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11 Participants
n=5 Participants
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Ethnicity (NIH/OMB)
Hispanic or Latino
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4 Participants
n=5 Participants
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Ethnicity (NIH/OMB)
Not Hispanic or Latino
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8 Participants
n=5 Participants
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Ethnicity (NIH/OMB)
Unknown or Not Reported
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0 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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2 Participants
n=5 Participants
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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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2 Participants
n=5 Participants
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Race (NIH/OMB)
White
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6 Participants
n=5 Participants
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Race (NIH/OMB)
More than one race
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1 Participants
n=5 Participants
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Race (NIH/OMB)
Unknown or Not Reported
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1 Participants
n=5 Participants
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PRIMARY outcome
Timeframe: Total drug exposure at time point zero to infinity on days 1, 7, & 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Area under the concentration versus time curve from 0 to infinity (AUC0-∞) following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 to measure the total drug exposure was analyzed by the linear up/log down trapezoidal rule using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA).
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Area Under the Concentration Versus Time Curve (AUC0-∞) for Rivaroxaban
Day 13 (phase 3)
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2226.38 hr*ng/ml
Standard Deviation 918.07
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Area Under the Concentration Versus Time Curve (AUC0-∞) for Rivaroxaban
Day 1 (phase 1)
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1049.19 hr*ng/ml
Standard Deviation 401.58
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Area Under the Concentration Versus Time Curve (AUC0-∞) for Rivaroxaban
Day 7 (phase 2)
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2274.3 hr*ng/ml
Standard Deviation 766.51
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PRIMARY outcome
Timeframe: 0 to 24 hours postdose on days 1, 7, and 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Area under the concentration versus time curve from (AUC0-24hr) following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 to measure total drug exposure was analyzed by the linear up/log down trapezoidal rule using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA).
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Area Under the Concentration Versus Time Curve (AUC0-24hr) for Rivaroxaban
Day 1 (phase 1)
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991.25 hr*ng/ml
Standard Deviation 378.02
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Area Under the Concentration Versus Time Curve (AUC0-24hr) for Rivaroxaban
Day 7 (phase 2)
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1929.78 hr*ng/ml
Standard Deviation 631.58
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Area Under the Concentration Versus Time Curve (AUC0-24hr) for Rivaroxaban
Day 13 (phase 3)
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1939 hr*ng/ml
Standard Deviation 748.78
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PRIMARY outcome
Timeframe: Up to 24 hours postdose on days 1, 7, and 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Maximum total plasma concentration (Cmax) following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). Cmax for rivaroxaban was obtained directly by visual inspection of the plasma concentration versus time over 24 hours postdose.
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Maximum Total Plasma Concentration (Cmax) for Rivaroxaban
Day 1 (phase 1)
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128.6 ng/mL
Standard Deviation 42.39
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Maximum Total Plasma Concentration (Cmax) for Rivaroxaban
Day 7 (phase 2)
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192.25 ng/mL
Standard Deviation 61.72
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Maximum Total Plasma Concentration (Cmax) for Rivaroxaban
Day 13 (phase 3)
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196.17 ng/mL
Standard Deviation 62.27
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PRIMARY outcome
Timeframe: Up to 24 hours postdose on days 1, 7, and 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Time to maximum plasma concentration for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). Tmax for rivaroxaban was obtained directly by visual inspection of the plasma concentration versus time over 24 hours postdose.
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Time to Maximum Plasma Concentration (Tmax) for Rivaroxaban
Day 1 (phase 1)
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2.5 Hours
Standard Deviation 1.38
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Time to Maximum Plasma Concentration (Tmax) for Rivaroxaban
Day 7 (phase 2)
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4.1 Hours
Standard Deviation 1.26
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Time to Maximum Plasma Concentration (Tmax) for Rivaroxaban
Day 13 (phase 3)
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3.02 Hours
Standard Deviation 1.29
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PRIMARY outcome
Timeframe: Up to 24 hours postdose on days 1, 7, and 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Terminal elimination half-life (t½) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). The apparent elimination rate constant (λZ) was determined by calculating the absolute value of the slope of the log-linear regression of at least 3 points of the plasma concentration-time plot. The t½ was calculated as 0.693/apparent elimination rate constant (λZ).
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Terminal Elimination Half-life (t½) for Rivaroxaban
Day 1 (phase 1)
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5.65 Hours
Standard Deviation 0.84
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Terminal Elimination Half-life (t½) for Rivaroxaban
Day 7 (phase 2)
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8.19 Hours
Standard Deviation 2.52
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Terminal Elimination Half-life (t½) for Rivaroxaban
Day 13 (phase 3)
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7.49 Hours
Standard Deviation 1.68
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PRIMARY outcome
Timeframe: Up to 24 hours postdose on days 1, 7, and 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Apparent oral clearance (CL/F) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). CL/F was calculated as 10 mg ÷ AUC0-tau for rivaroxaban.
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Apparent Oral Clearance (CL/F) for Rivaroxaban
Day 1 (phase 1)
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11.04 L/hr
Standard Deviation 4.69
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Apparent Oral Clearance (CL/F) for Rivaroxaban
Day 7 (phase 2)
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4.92 L/hr
Standard Deviation 1.77
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Apparent Oral Clearance (CL/F) for Rivaroxaban
Day 13 (phase 3)
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5.19 L/hr
Standard Deviation 2.11
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PRIMARY outcome
Timeframe: Up to 24 hours postdose on days 1, 7, and 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Apparent volume of distribution (V/F) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA).
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Apparent Volume of Distribution (V/F) for Rivaroxaban
Day 7 (phase 2)
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56.22 Liter
Standard Deviation 23.07
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Apparent Volume of Distribution (V/F) for Rivaroxaban
Day 13 (phase 3)
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52.84 Liter
Standard Deviation 16.32
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Apparent Volume of Distribution (V/F) for Rivaroxaban
Day 1 (phase 1)
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89.94 Liter
Standard Deviation 42.32
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PRIMARY outcome
Timeframe: Up to 24 hours postdose on days 1, 7, and 13Population: All participants who completed at least one intensive pharmacokinetic visit were included in the pharmacokinetics analysis
Minimum total plasma concentration (Cmin) for Rivaroxaban following a single dose of rivaroxaban 10 mg orally on days 1, 7, and 13 was analyzed using noncompartmental methods with Phoenix WinNonlin® (version 8.0; Pharsight Corporation, Mountain View, CA). Cmin for rivaroxaban was obtained directly by visual inspection of the plasma concentration versus times over 24 hours postdose.
Outcome measures
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 Participants
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Minimum Total Plasma Concentration (Cmin) for Rivaroxaban
Day 1 (phase 1)
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6.93 ng/mL
Standard Deviation 3.43
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Minimum Total Plasma Concentration (Cmin) for Rivaroxaban
Day 7 (phase 2)
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27.32 ng/mL
Standard Deviation 13.25
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Minimum Total Plasma Concentration (Cmin) for Rivaroxaban
Day 13 (phase 3)
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24.43 ng/mL
Standard Deviation 14.38
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Adverse Events
Pharmacokinetic Study in Healthy Volunteers
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Pharmacokinetic Study in Healthy Volunteers
n=12 participants at risk
Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.
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Cardiac disorders
Dizziness
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16.7%
2/12 • 23 days
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Gastrointestinal disorders
Nausea
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8.3%
1/12 • 23 days
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General disorders
Fatigue
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8.3%
1/12 • 23 days
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Investigations
Activated partial thromboplastin time prolonged
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8.3%
1/12 • 23 days
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Investigations
Blood bicarbonate decreased
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41.7%
5/12 • 23 days
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Investigations
Blood bilirubin increased
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8.3%
1/12 • 23 days
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Investigations
Blood phosphorus decreased
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8.3%
1/12 • 23 days
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Investigations
Blood potassium decreased
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8.3%
1/12 • 23 days
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Investigations
Glomerular filtration rate decreased
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16.7%
2/12 • 23 days
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Investigations
Haemoglobin decreased
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8.3%
1/12 • 23 days
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Musculoskeletal and connective tissue disorders
Neck pain
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8.3%
1/12 • 23 days
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Nervous system disorders
Headache
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16.7%
2/12 • 23 days
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place