In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC 50 ) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of oncedaily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation.
Purpose of the studyTMC278 is a next-generation investigational NNRTI with potent and sustained efficacy through 96 weeks in ARVnaïve patients [1]. The current trial evaluated the PK interaction between omeprazole and TMC278. Omeprazole increases gastric pH, which can affect the solubility and gastro-intestinal absorption of TMC278. Furthermore, TMC278 has been shown to induce CYP2C19 in vitro, which may influence the omeprazole PK. MethodsThis was an open-label, randomized, 2-way crossover trial in 16 HIV-negative volunteers. In two sessions, separated by a 14-day washout, participants received TMC278 150 mg QD alone (11 days), and omeprazole 20 mg QD (22 days) with co-administration of TMC278 150 mg QD (day 12-22). All treatments were taken following breakfast. Steady-state 24-hr PK profiles of TMC278 were assessed on the last day of each session and steady-state 24-hr PK profiles of omeprazole and its metabolite 5-hydroxy(OH)-omeprazole (formed via CYP2C19) were assessed without (day 11) and with (day 22) co-administration of TMC278. PK parameters were calculated using non-compartmental analysis. The AUC 24 h ratio of 5-OHomeprazole to omeprazole was used as a surrogate marker of CYP2C19 activity. Least square (LS) means and associated 90% CI of treatment ratios (test/reference) were calculated based on log-transformed PK parameters.When combined with omeprazole, the TMC278 steadystate AUC 24 h decreased by 40% (LS mean ratio 0.60, 90% CI 0.51-0.71) compared to administration of TMC278 alone, and the steady-state C max and C min decreased by 40% (0.60, 90% CI 0.48-0.73) and 33% (0.67, 90% CI 0.58-0.78), respectively. TMC278 at steady state decreased the omeprazole AUC 24 h by 14% (0.86, 90%CI 0.76-0.97). Repeated doses of TMC278 resulted in a 27% increase of the AUC 24 h ratio of 5-OH-omeprazole to omeprazole (1.27, 90%CI 1.18-1.36). The latter suggests weak induction of CYP2C19 by TMC278 150 mg QD, an effect which will likely be less at lower doses, and is unlikely to result in clinically relevant interactions. TMC278 alone or in combination with omeprazole was generally well tolerated. No grade 3 or 4 adverse events (AEs) and no serious AEs were reported. There were no discontinuations due to AEs. ConclusionThese results confirm the pH-dependent bioavailability of TMC278 and indicate that proton pump inhibitors and TMC278 25 mg QD (selected dose for Phase III) should not be co-administered. As an alternative, H 2 -antagonists can be used, if taken 12 hours before or 4 hours after TMC278 [2].
7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK
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