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Tenofovir Exposure Moderately Higher With vs Without Cobicistat in Healthy Volunteers
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14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
Tenofovir maximum concentration and area under the concentration-time curve (AUC) were moderately higher when tenofovir disoproxil fumarate (TDF) was administered with the boosting agent cobicistat than when given alone to healthy volunteers [1]. A parallel study found that TDF had no impact on cobicistat concentrations.
Cobicistat has been licensed for first-line therapy as part of the fixed-dose combination Stribild, which includes the integrase inhibitor elvitegravir plus TDF/emtricitabine [2]. Ongoing trials are evaluating cobicistat as a booster for atazanavir or darunavir, and licensing is expected soon. Cobicistat is an inhibitor of the transporter P-glycoprotein (P-gp), while the prodrug of TDF is a P-gp substrate. To determine the impact of each agent upon the other, Gilead Sciences researchers conducted this randomized, two-cohort, crossover study in 46 healthy volunteers.
The study involved 32 volunteers in cohort 1 and 14 in cohort 2. Each cohort had two 7-day treatment periods separated by a washout. Cohort 1 took 150 mg of cobicistat once daily alone or with 300 mg of TDF once daily in the two treatment periods. Cohort 2 took 300 mg of TDF once daily alone or in combination with 150 mg of cobicistat once daily in the two treatment periods. The researchers measured drug levels on the first and last day of each treatment period.
Most participants in cohorts 1 (72%) and 2 (64%) were men. Respective proportions of whites were 59% and 79%. Age averaged 33 in both cohorts, while weight averaged 79.1 kg in cohort 1 and 75.8 kg in cohort 2.
All but 1 of 46 study participants completed both treatment periods. One person dropped out because of grade 2 rash while taking TDF. No grade 3 or 4 adverse events were observed, and both agents were generally well tolerated. Renal function measures were within normal ranges for all participants. Estimated glomerular filtration rate decreased slightly, by approximately 10 mL/min, during cobicistat administration, an effect expected because cobicistat inhibits creatinine secretion by inhibiting the renal MATE-1 transporter.
After multiple doses of cobicistat plus TDF versus cobicistat alone in cohort 1, TDF did not affect pharmacokinetics of cobicistat, as indicated by geometric mean ratios (cobicistat-TDF combined/cobicistat alone) of 100 (90% confidence interval [CI] 95.4 to 105) for maximum concentration, 100 (90% CI 94.7 to 106) for AUC, and 107 (90% CI 94.1 to 121) for trough concentration.
When cobicistat and TDF were combined in cohort 2, tenofovir maximum concentration was 55% higher than with TDF alone, as indicated by a geometric mean ratio of 155 (90% CI 134 to 178). Tenofovir AUC was moderately higher with cobicistat plus TDF versus TDF alone, as indicated by a geometric mean ratio 123 (90% CI 116 to 139). Tenofovir trough concentration was 25% higher with than without cobicistat (geometric mean ratio 125, 90% CI 116 to 136). The Gilead team noted those results are consistent with cobicistat inhibition of intestinal P-gp-mediated efflux of TDF.
Tenofovir half-life was similar with cobicistat plus TDF versus TDF alone, a result indicating that cobicistat did not change tenofovir elimination.
The researchers noted that moderately higher tenofovir exposures when TDF is taken with cobicistat are comparable to higher tenofovir levels in historical data with Stribild or when TDF is taken with a ritonavir-boosted protease inhibitor.
References
1. Custodio J, Garner W, Jin F, et al. Evaluation of the drug interaction potential between the pharmacokinetic enhancer cobicistat and tenofovir disoproxil fumarate in healthy subjects. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_07.
2. STRIBILD prescribing information. http://services.gileadhiv.com/stribild/pdf/pi
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