Pharmacokinetics of Cenicriviroc following 100- or 200-mg Once-daily Dosing with Open-label Emtricitabine/Tenofovir in HIV 1+ Subjects Enrolled in a Phase 2b Study
David Martin*1, M Beliveau2, J-F Marier2, R Driz1, and S Palleja1
1Tobira Therapeutics, Inc, Manalapan, NJ, US and 2Pharsight, Montreal, Canada
Background: Cenicriviroc (CVC) is a potent, once-daily oral CCR5/CCR2 receptor antagonist. Study 202 is an ongoing, randomized, double-blind trial to evaluate the efficacy and safety of 100- and 200-mg once-daily doses of CVC vs once-daily efavirenz, each with open-label emtricitabine/tenofovir (FTC/TDF). A new 50-mg tablet formulation was utilized for this study and a planned interim analysis of CVC in the first 25 enrolled patients (of a study total of 150 patients) was performed to evaluate the steady state pharmacokinetics of this new formulation. The exposure-effect relationship for CVC was previously established in a 10-day monotherapy study with an estimated Emax of –1.43 log10 copies/mL and an IC50 of 13.1 ng/mL. The new 50-mg formulation was expected to provide average concentration (Cavg) for CVC of at least 55 ng/mL or ~80% of the estimated Emax .
Methods: Treatment assignments were randomized 2:2:1, respectively. Pharmacokinetic analysis was conducted by an unblinded, independent biometrics group while the sponsor, investigators, and patients remain blinded. Blood samples were collected over a 24-hour period on day 14. Noncompartmental analysis of CVC was performed to assess steady-state pharmcokinet parameters. The area under the curve (AUC0-t), average concentration (Cavg), maximum concentration (Cmax), minimum concentration (Cmin) and time to maximum concentrations (Tmax) of CVC were derived.
Results: Given the short duration of treatment and the blinded nature of the analysis, no safety or efficacy data are available. A total of 18 CVC-treated patients had evaluable pharmacokinetic data. Arithmetic mean (CV%) Cavg values of CVC for the 100- and 200-mg doses were 94.3 (44.8%) and 234 (44.4%) ng/mL, respectively. Mean (CV%) Cmin values for the 100- and 200-mg doses were 47.5 (57.0%) and 102 (58.5%) ng/mL, respectively. Median Tmax for the the 100- and 200-mg doses were observed at 5.0 and 6.0 hours, respectively. Overall, CVC was well absorbed following repeat dosing of 100- and 200-mg once daily, and exposure increased in a dose proportional manner. The exposure to CVC for the 100- and 200-mg dose was ~88% and 95%, respectively, of the estimated Emax.
Conclusions: The new 50-mg formulation of CVC was well absorbed following repeat dosing of 100- and 200-mg once-daily, with average and minimum plasma concentrations in the expected therapeutic range for the molecule.