The Pharmokinetic Interactions of HCV Protease Inhibitor TMC435 with RPV, TDF, EFV, or RAL in Health Volunteers
Sivi Ouwerkerk-Mahadevan*1, V Sekar2, M Peeters1, and M Beumont-Mauviel1
1Tibotec BVBA, Beerse, Belgium and 2Tibotec Inc, Titusville, NJ, US
Background: A significant proportion of HIV+ patients are co-infected with hepatitis C virus (HCV) and may require treatment with HIV and HCV antiviral agents. Two open-label, randomized, 2-panel, 3-way crossover studies were conducted in healthy subjects to investigate pharmacokinetic interactions between the investigational oral, once-daily HCV NS3/4A protease inhibitor TMC435 and rilpivirine (RPV, TMC278) or tenofovir (given as tenofovir disoproxil fumarate [TDF]) in study TMC435—C123, or efavirenz (EFV) or raltegravir (RAL) in study TMC435—C114.
Methods: Subjects received, in a randomized fashion, either TMC435 (150 mg once daily), RPV (25 mg once daily), TDF (300 mg once daily), EFV (600 mg once daily), or RAL (400 mg twice daily) alone, or TMC435 and each ARV combined. Agents were received for 11, 7, 14, or 7 days (Study 1 RPV, Study 1 TDF, Study 2 EFV, and Study 2 RAL, respectively) under fed conditions, except for EFV (2 hours after food). Adequate washout periods were respected between panels. Pharmacokinetic parameters were determined on the final day of administration over 24 hours (all agents in Study 1), 96 h (TMC435 in Study 2), 94 hours (EFV in Study 2), or 12 hours (RAL in Study 2). Safety and tolerability were monitored throughout. Least square means and 90% confidence intervals of treatment ratios (test/reference) were calculated for the log-transformed AUCtau and Cmin.
Results: We enrolled 48 subjects to each study (24 per panel). The least square means ratios (90%CI) for pharmacokinetic parameters are shown in the table. No adverse event–related treatment discontinuations or serious adverse events were reported in these trials.
Conclusions: Dose adjustments are not required when RPV, TDF, or RAL are co-administered with TMC435. If efficacy and safety of these combinations are confirmed, they may provide convenient once-daily treatment options for HCV/HIV-co-infected patients. Co-administration of TMC435 and EFV should be avoided due to the observed decrease in TMC435 exposure in the presence of EFV.