A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV‐positive subjects

AIMS Maraviroc (UK‐427 857), an antagonist of the CCR5 receptor with potent anti‐HIV activity, was recently approved for use in treatment‐experienced patients infected with CCR5‐tropic HIV‐1. The aim of this study was to evaluate the effect of selected commonly used antiretroviral therapy (ART) combinations on the pharmacokinetics of a single oral dose of maraviroc 300 mg in HIV‐positive subjects compared with historical controls. METHODS In this study, four cohorts of HIV‐positive patients (n = 8 each) receiving one of the following combination therapies were recruited: cohort 1 – efavirenz + Combivir® (lamivudine/zidovudine); cohort 2 – efavirenz + didanosine + tenofovir; cohort 3 – nevirapine + lamivudine + tenofovir; cohort 4 – Kaletra® (lopinavir/ritonavir) + stavudine + lamivudine. Subjects continued on their prescribed ART and also received a single oral dose of maraviroc 300 mg. Serial blood samples and urine for determination of maraviroc pharmacokinetics were collected over 12 h postdose. Plasma pharmacokinetic parameters from this study were compared with historical data generated in HIV‐positive subjects receiving maraviroc monotherapy in a Phase IIa study. RESULTS A total of 29 subjects were recruited (eight each in cohorts 1–3, and five in cohort 4). The geometric mean ratios for AUC12 and Cmax for each treatment group compared with maraviroc monotherapy were: 47% and 67% (cohort 1); 48% and 76% (cohort 2); 101% and 154% (cohort 3); and 265% and 180% (cohort 4), respectively. Tmax was similar in all treatment groups. Mean values for renal clearance ranged from 8.2 l h−1 (cohort 1) to 13.2 l h−1 (cohort 4). There were no renal clearance data collected in the comparator study. CONCLUSIONS The results of this study support those previously seen in healthy volunteer studies that showed that efavirenz reduces maraviroc exposure, whereas lopinavir/ritonavir increases maraviroc exposure. These data also suggest that nevirapine does not lead to a clinically significant effect on maraviroc pharmacokinetics.