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Pharmacokinetics of etravirine are not affected by sex, age, race, treatment duration or use of enfuvirtide in HIV-1-infected subjects
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Reported by Jules Levin
IAC, Aug 3-8, 2008, Mexico City
Thomas N Kakuda,1 Monika Scholler-Gyure,2 Monika Peeters,2 Chris Corbett,2 Goedele De Smedt,2 Brian J Woodfall,2 Richard MW Hoetelmans2
1Tibotec Inc., Yardley, PA, USA; 2Tibotec BVBA, Mechelen, Belgium
AUTHOR DISCUSSION & CONCLUSIONS
ETR has moderate-to-high inter and intrasubject variability
- intersubject variability probably due to metabolism via - multiple CYP isozymes (i.e. CYP3A, 2C9 and 2C19), adherence, concomitant medications (e.g. TDF) and/or hepatitis coinfection status
- intrasubject variability probably due to CYP2C19,- 6,7 adherence, concomitant medications and/or food effects.
ETR pharmacokinetics do not vary by sex, age, race, use of ENF, or treatment duration.
TDF decreases ETR AUC12h by about 26%
- consistent with interaction studies in healthy volunteers
- mechanism unknown
· possible effect of TDF on CYP2C19?
Hepatitis coinfection increases ETR AUC12h about 1.35-fold
- change in CL/F was negligible (+8.3%) in subjects with HBV, whereas a 24% decrease in CL/F was observed in subjects with HCV
- no obvious difference in concomitant medications or baseline demographics
- mechanism unknown.
ETR AUC12h was slightly higher with decreasing weight or increasing adherence.
No relationship between pharmacokinetics and efficacy or safety have been demonstrated in the DUET trials8
- no dose adjustments are needed for TDF, hepatitis coinfection status or weight.
ABSTRACT
Background
Etravirine (ETR, formerly TMC125) is an FDA-approved next-generation NNRTI. In-vitro, ETR has potent activity against both wild-type and NNRTI-resistant HIV. ETR was superior to placebo in the proportion of treatment-experienced HIV-1-infected subjects achieving viral load <50 copies/mL at Week 48 from two ongoing trials (DUET-1 and DUET-2).
Methods
A two-compartment model with sequential zero-order and first-order absorption including lag-time was developed for population pharmacokinetics analyses. Area under the plasma concentration-time curve from time of administration to 12 hours after dosing (AUC12h) and predose plasma concentration (C0h) were individually estimated from sparse sampling over 48 weeks using Bayesian feedback. The effect of sex, age, race, weight, adherence, enfuvirtide (ENF) or tenofovir (TDF) use, and hepatitis B or C coinfection on ETR AUC12h or C0h was assessed using analysis of covariance (ANCOVA). The effect of treatment duration was assessed graphically.
Results
ETR population pharmacokinetics were estimated in575 subjects. Mean (standard deviation [SD]) ETR AUC12h and C0h were 5,506 (4,710) ng·h/mL and 393 (391) ng/mL, respectively.
Inter and intrasubject variability was 60% and 40%, respectively. Mean (SD) AUC12h in 57 women was 6,027 (3,591) ng·h/mL compared to 5,449 (4,817) ng·h/mL in 518 men (p=0.1976).
Exposure in Caucasians (n=360), Blacks (n=67), Hispanics (n=56) and Asians (n=7) was not significantly different (p=0.2272).
ETR AUC12h increased with increasing adherence (p=0.0187) or decreasing weight (p=0.0490).
Use of ENF had no effect on AUC12h (p=0.8048);
TDF use was associated with a 26% lower AUC12h (p=0.0005).
Hepatitis coinfection was associated with a 1.35-fold increase in AUC12h (p=0.0028).
There was a trend towards higher ETR exposure with increased age (p=0.0645).
Graphically, plasma concentrations over 24 weeks revealed no time-dependent effects.
Conclusions
ETR pharmacokinetics do not vary by sex, race, age or use of ENF. TDF was associated with lower, whereas hepatitis coinfection with higher, ETR exposure. Exposures were slightly higher in subjects with lower weight and greater adherence. No dose adjustments for ETR are necessary for these covariates. ETR pharmacokinetics were not time-dependent.
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