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Trial Outcomes & Findings for Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics (NCT NCT00668395)

NCT ID: NCT00668395

Last Updated: 2014-09-26

Results Overview

Efavirenz clearance is a measure of rate of elimination of the drug from the body. We used this measure to evaluate differences in rate of elimination of efavirenz at a single dose and after multiple dosing within three CYP2B6 genotypes (CYP2B6\*1/\*1, \*1/\*6 and CYP2B6\*6/\*6). Efavirenz clearance was measured in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6) and slow metabolizer (CYP2B6\*6/\*6) at a single 600 mg oral dose of efavirenz and then after multiple dosing (autoinduction), i.e., the administration of efavirenz (600 mg/day) for 17 days. Single and multiple dose efavirenz clearance was measured and compared to determine the extent of autoinduction within this genotype group.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

73 participants

Primary outcome timeframe

Efavirenz clearance at single dose and multiple dose stratified by CYP2B6 genotypes

Results posted on

2014-09-26

Participant Flow

Healthy subjects from self -referrals, campus fliers, Indiana University's Clinical Trials Webpage, community bulletin boards and newspaper were enrolled. All subjects were studied at the Indiana Clinical Research Center. Recruitment was completed within 3 years (8/20/07 to 4/15/10).

The study was initially designed to enroll subjects with prespecified CYP2B6 genotype (\*1/\*1, \*1/\*6, and \*6/\*6; n=20 each), but it was later modified in which subjects were enrolled without pregenotype information and genotype was performed post-hoc.

Participant milestones

Participant milestones
Measure
CYP2B6*1/*1 Genotype Group
1. Efavirenz clearance following a single 600 mg oral dose of efavirenz and after multiple doses of efavirenz (600 mg/day orally for 17 days) was analyzed in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6 genotype) and slow metabolizer (CYP2B6\*6/\*6). During the study, the design was slightly modified to sequentially enroll instead of allocation based on specific genotype, and genotype effect was analyzed post-hoc. 2. The activities of CYP1A2, CYP2C9, CYP2C19, CYP3A were determined in all subjects (without regard to CYP2B6 genotype) using the metabolism of isoform selective probe substrates during the single dose (600 mg efavirenz orally) and after intake of multiple doses of efavirenz (600 mg/day efavirenz orally for 17 days) to assess efavirenz mediated drug interactions.
CYP2B6*1/*6 Genotype Group
1. Efavirenz clearance following a single 600 mg oral dose of efavirenz and after multiple doses of efavirenz (600 mg/day orally for 17 days) was analyzed in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6 genotype) and slow metabolizer (CYP2B6\*6/\*6). During the study, the design was slightly modified to sequentially enroll instead of allocation based on specific genotype, and genotype effect was analyzed post-hoc. 2. The activities of CYP1A2, CYP2C9, CYP2C19, CYP3A were determined in all subjects (without regard to CYP2B6 genotype) using the metabolism of isoform selective probe substrates during the single dose (600 mg efavirenz orally) and after intake of multiple doses of efavirenz (600 mg/day efavirenz orally for 17 days) to assess efavirenz mediated drug interactions.
CYP2B6*6/*6 Genotype Group
1. Efavirenz clearance following a single 600 mg oral dose of efavirenz and after multiple doses of efavirenz (600 mg/day orally for 17 days) was analyzed in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6 genotype) and slow metabolizer (CYP2B6\*6/\*6). During the study, the design was slightly modified to sequentially enroll instead of allocation based on specific genotype, and genotype effect was analyzed post-hoc. 2. The activities of CYP1A2, CYP2C9, CYP2C19, CYP3A were determined in all subjects (without regard to CYP2B6 genotype) using the metabolism of isoform selective probe substrates during the single dose (600 mg efavirenz orally) and after intake of multiple doses of efavirenz (600 mg/day efavirenz orally for 17 days) to assess efavirenz mediated drug interactions.
Overall Study
STARTED
45
22
6
Overall Study
COMPLETED
39
16
5
Overall Study
NOT COMPLETED
6
6
1

Reasons for withdrawal

Reasons for withdrawal
Measure
CYP2B6*1/*1 Genotype Group
1. Efavirenz clearance following a single 600 mg oral dose of efavirenz and after multiple doses of efavirenz (600 mg/day orally for 17 days) was analyzed in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6 genotype) and slow metabolizer (CYP2B6\*6/\*6). During the study, the design was slightly modified to sequentially enroll instead of allocation based on specific genotype, and genotype effect was analyzed post-hoc. 2. The activities of CYP1A2, CYP2C9, CYP2C19, CYP3A were determined in all subjects (without regard to CYP2B6 genotype) using the metabolism of isoform selective probe substrates during the single dose (600 mg efavirenz orally) and after intake of multiple doses of efavirenz (600 mg/day efavirenz orally for 17 days) to assess efavirenz mediated drug interactions.
CYP2B6*1/*6 Genotype Group
1. Efavirenz clearance following a single 600 mg oral dose of efavirenz and after multiple doses of efavirenz (600 mg/day orally for 17 days) was analyzed in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6 genotype) and slow metabolizer (CYP2B6\*6/\*6). During the study, the design was slightly modified to sequentially enroll instead of allocation based on specific genotype, and genotype effect was analyzed post-hoc. 2. The activities of CYP1A2, CYP2C9, CYP2C19, CYP3A were determined in all subjects (without regard to CYP2B6 genotype) using the metabolism of isoform selective probe substrates during the single dose (600 mg efavirenz orally) and after intake of multiple doses of efavirenz (600 mg/day efavirenz orally for 17 days) to assess efavirenz mediated drug interactions.
CYP2B6*6/*6 Genotype Group
1. Efavirenz clearance following a single 600 mg oral dose of efavirenz and after multiple doses of efavirenz (600 mg/day orally for 17 days) was analyzed in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6 genotype) and slow metabolizer (CYP2B6\*6/\*6). During the study, the design was slightly modified to sequentially enroll instead of allocation based on specific genotype, and genotype effect was analyzed post-hoc. 2. The activities of CYP1A2, CYP2C9, CYP2C19, CYP3A were determined in all subjects (without regard to CYP2B6 genotype) using the metabolism of isoform selective probe substrates during the single dose (600 mg efavirenz orally) and after intake of multiple doses of efavirenz (600 mg/day efavirenz orally for 17 days) to assess efavirenz mediated drug interactions.
Overall Study
Withdrawal by Subject
4
4
1
Overall Study
Adverse Event
1
1
0
Overall Study
Physician Decision
1
1
0

Baseline Characteristics

Effects of CYP2B6 Genetic Polymorphisms on Efavirenz Pharmacokinetics

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
CYP2B6*1/*1
n=45 Participants
Normal metabolizer
CYP2B6*1/*6
n=22 Participants
Intermediate metabolizer
CYP2B6*6/*6
n=6 Participants
Slow metabolizer
Total
n=73 Participants
Total of all reporting groups
Age, Continuous
28.3 years
STANDARD_DEVIATION 10.2 • n=5 Participants
29.5 years
STANDARD_DEVIATION 9.9 • n=7 Participants
23.2 years
STANDARD_DEVIATION 3.9 • n=5 Participants
28.2 years
STANDARD_DEVIATION 9.8 • n=4 Participants
Sex: Female, Male
Female
17 Participants
n=5 Participants
6 Participants
n=7 Participants
4 Participants
n=5 Participants
27 Participants
n=4 Participants
Sex: Female, Male
Male
28 Participants
n=5 Participants
16 Participants
n=7 Participants
2 Participants
n=5 Participants
46 Participants
n=4 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
0 Participants
n=4 Participants
Race (NIH/OMB)
Asian
0 Participants
n=5 Participants
2 Participants
n=7 Participants
0 Participants
n=5 Participants
2 Participants
n=4 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
0 Participants
n=4 Participants
Race (NIH/OMB)
Black or African American
9 Participants
n=5 Participants
4 Participants
n=7 Participants
3 Participants
n=5 Participants
16 Participants
n=4 Participants
Race (NIH/OMB)
White
35 Participants
n=5 Participants
14 Participants
n=7 Participants
3 Participants
n=5 Participants
52 Participants
n=4 Participants
Race (NIH/OMB)
More than one race
1 Participants
n=5 Participants
2 Participants
n=7 Participants
0 Participants
n=5 Participants
3 Participants
n=4 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
0 Participants
n=4 Participants
BMI
23.9 kg/m2
STANDARD_DEVIATION 3.5 • n=5 Participants
25.4 kg/m2
STANDARD_DEVIATION 4.1 • n=7 Participants
22.0 kg/m2
STANDARD_DEVIATION 3.0 • n=5 Participants
24.2 kg/m2
STANDARD_DEVIATION 3.7 • n=4 Participants
Body weight
73.6 kg
STANDARD_DEVIATION 13 • n=5 Participants
77.2 kg
STANDARD_DEVIATION 14.1 • n=7 Participants
65 kg
STANDARD_DEVIATION 5.3 • n=5 Participants
74 kg
STANDARD_DEVIATION 13.4 • n=4 Participants

PRIMARY outcome

Timeframe: Efavirenz clearance at single dose and multiple dose stratified by CYP2B6 genotypes

Efavirenz clearance is a measure of rate of elimination of the drug from the body. We used this measure to evaluate differences in rate of elimination of efavirenz at a single dose and after multiple dosing within three CYP2B6 genotypes (CYP2B6\*1/\*1, \*1/\*6 and CYP2B6\*6/\*6). Efavirenz clearance was measured in normal metabolizer of CYP2B6 (CYP2B6\*1/\*1 genotype), intermediate metabolizer (CYP2B6\*1/\*6) and slow metabolizer (CYP2B6\*6/\*6) at a single 600 mg oral dose of efavirenz and then after multiple dosing (autoinduction), i.e., the administration of efavirenz (600 mg/day) for 17 days. Single and multiple dose efavirenz clearance was measured and compared to determine the extent of autoinduction within this genotype group.

Outcome measures

Outcome measures
Measure
CYP2B6*1/*1
n=38 Participants
Normal metabolizer
CYP2B6*1/*6
n=17 Participants
Intermediate metabolizer
CYP2B6*6/*6
n=5 Participants
Slow metabolizer
Effect of CYP2B6 Genotype on Efavirenz Clearance
Single efavirenz dose
93.35 ml/h/kg
Standard Deviation 21.74
76.08 ml/h/kg
Standard Deviation 21.59
51.03 ml/h/kg
Standard Deviation 12.06
Effect of CYP2B6 Genotype on Efavirenz Clearance
Multiple efavirenz dose
50.05 ml/h/kg
Standard Deviation 36.04
119.90 ml/h/kg
Standard Deviation 39.15
80.12 ml/h/kg
Standard Deviation 38.12

Adverse Events

CYP2B6*1/*1

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

CYP2B6*1/*6

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

CYP2B6*6/*6

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Zeruesenay Desta, PhD

Indiana University School of Medicine

Phone: 317-274-2823

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place