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Tenofovir, Hepatitis, and Weight Moderately Affect Etravirine Levels
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9th International Workshop on Clinical Pharmacology of HIV Therapy
April 7-9, 2008
New Orleans
Mark Mascolini
Tenofovir lowers levels of etravirine (TMC125), while hepatitis coinfection and lighter weight raise concentrations of the nonnucleoside [1]. But none of these changes were large enough to require a change in etravirine dosing. Gender and race had no impact on etravirine exposure.
Thomas Kakuda and Tibotec colleagues analyzed etravirine pharmacokinetics (PKs) in people enrolled in the DUET trials, which combined etravirine with darunavir/ritonavir and other antiretrovirals for patients with resistance to nonnucleosides and protease inhibitors [2,3]. All study participants had etravirine levels measured at week 4 and randomly at weeks 8, 12, and 24. A PK substudy involved 25 people who had intensive sampling at weeks 4 and 24.
In all 525 etravirine-treated DUET enrollees, median 12-hour etravirine area under the concentration-time curve (AUC) measured 4380 ng/h/mL and ranged from 458 to 59,084 ng/h/mL, while median etravirine trough stood at 298 ng/mL and ranged from 2 to 4852 ng/mL. Interpatient variability measured 60% and intrapatient variability 40%. Kakuda attributed the interpatient variability to varying metabolism of etravirine, differing adherence, concomitant drugs (including tenofovir), and hepatitis virus coinfection.
Etravirine AUC averaged 6848 ng/h/mL in 139 people not taking tenofovir and 5079 ng/h/mL in 436 people taking tenofovir, a significant 26% decrease (P = 0.0005). The difference reflects etravirine PK findings in healthy volunteers. Although Kakuda reported that the mechanism for this effect remains unknown, he suggested tenofovir's effect on the CYP2C19 drug-metabolizing enzyme may be involved.
In 475 people without hepatitis B or C (HBV or HCV), etravirine AUC averaged 5333 ng/h/mL, compared with 7207 ng/h/mL in 69 people with hepatitis, a significant 35% increase (P = 0.0028). Etravirine clearance was similar in people with and without HBV, but clearance was 24% lower in HCV-infected people than in those without HCV. The investigators saw no obvious differences in concomitant medications or baseline demographics that would explain these PK differences, and they suggested no mechanism.
Etravirine levels were significantly higher in people with good adherence (P = 0.0187) and lower weight (P = 0.049). Kakuda saw a trend to higher etravirine exposure with older age (P = 0.0645).
In 57 women etravirine AUC averaged 6027 ng/h/mL, compared with 5449 ng/h/mL in 518 men, a nonsignificant difference (P = 0.20). Concentrations of the nonnucleoside did not differ significantly among 360 whites, 57 blacks, 56 Hispanics, and 7 Asians.
In substudy participants median etravirine trough, peak, 12-hour concentration, and 12-hour AUC did not vary significantly from week 4 to week 24. The geometric mean ratio between week 4 and week 24 AUC was 0.98.
Pooled analysis of week 24 DUET-1 and -2 results uncovered no link between etravirine PKs and its efficacy or safety [4].
References
1. Kakuda TN, Scholler-Gyure M, Peeters M, et al. Pharmacokinetics of etravirine are not affected by sex, age, race, use of enfuvirtide or treatment duration in HIV-1 infected patients. 9th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2008. New Orleans. Abstract O16.
2. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.
3. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.
4. Kakuda T, Wade J, Snoeck E, et al. Pharmacokinetics and pharmacodynamics of the NNRTI TMC125 in treatment-experienced HIV-1-infected patients: pooled 24-week results of DUET-1 and DUET-2. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 762.
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