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
ObjectivesThe aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection. MethodsThis phase 3b, open-label study enrolled HIV-1-infected pregnant women (18-26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/ 150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24-28 and 34-38 weeks of gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration-time curve over 24 h (AUC 24 h ), maximum plasma concentration (C max ) and minimum plasma concentration (C min )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated. ResultsSeven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC 24 h , 50-56% lower; C max , 37-49% lower; C min , 89-92% lower); unbound darunavir exposure was also reduced (AUC 24 h , 40-45% lower; C max , 32-41% lower; C min , 88-92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC 24 h , 49-63% lower; C max , 27-50% lower; C min , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants. ConclusionsIn view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.
ObjectivesA week 48 efficacy and safety analysis with respect to gender and race was conducted using pooled data from the phase III, double-blind, double-dummy efficacy comparison in treatment-naïve, HIV-infected subjects of TMC278 and efavirenz (ECHO) and TMC278 against HIV, in a once-daily regimen versus efavirenz (THRIVE) trials. MethodsTreatment-naïve, HIV-1-infected adults were randomized to receive rilpivirine (RPV; TMC278) 25 mg once a day (qd), or efavirenz (EFV) 600 mg qd, plus tenofovir/emtricitabine (ECHO) or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (THRIVE). ResultsA total of 1368 participants (76% male and 61% White, of those with available race data) were randomized and treated. No gender-related differences in response rate (percentage of patients with HIV-1 viral load < 50 HIV-1 RNA copies/mL, using an intent-to-treat, time-to-loss-ofvirological-response algorithm) were observed (RPV: men, 85%; women, 83%; EFV: men, 82%; women, 83%). Response rates were lower in Black compared with Asian and White participants (RPV: 75% vs. 95% and 85%, respectively; EFV: 74% vs. 93% and 83%, respectively); this finding was mostly a result of higher discontinuation and virological failure rates in Black patients. Safety findings were generally similar across race and gender subgroups. However, nausea occurred more commonly in women than in men in both treatment groups. In men, diarrhoea was more frequent in the EFV group, and abnormal dreams/nightmares were more frequent in men in both the EFV and RPV groups. ConclusionsOverall response rates were high for both RPV and EFV. No gender differences were observed. However, response rates were lower among Black patients, regardless of treatment group. Gender appeared to influence the incidence of gastrointestinal adverse events and abnormal dreams/nightmares for both treatments.
7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK
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