Renal insufficiency has no effect on the pharmacokinetics of vicriviroc in a ritonavir-containing regimen.

BACKGROUND AND

objectiveVicriviroc is a small-molecule CCR5 antagonist currently in development for the treatment of HIV in patients on a regimen containing a ritonavir-boosted protease inhibitor. As renal disease and renal dysfunction are prevalent in the HIV-infected population, patients with varying degrees of renal insufficiency may receive vicriviroc, which is metabolized by cytochrome P450 (CYP) 3A4. The present study therefore examined the impact of renal insufficiency on the pharmacokinetics and safety of vicriviroc alone and in the presence of ritonavir, a strong CYP3A4 inhibitor. SUBJECTS AND

methodsThis study was an open-label, randomized, two-treatment crossover trial conducted in HIV-negative subjects with haemodialysis-dependent end-stage renal disease (ESRD) and healthy subjects with normal renal function matched by age, height, bodyweight and sex. Subjects received a single dose of vicriviroc 75 mg alone in one period, and in another period they received a single dose of vicriviroc 15 mg after 4 days of ritonavir 100 mg once daily. Ritonavir treatment was then continued for an additional 13 days. The two trial periods were separated by an interval of at least 3 weeks. The primary endpoints were the log-transformed area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C(max)), and the 90% confidence intervals (CIs) of the mean differences between subjects with ESRD and matched healthy subjects. The protocol provided the option of dose modification and further study if the vicriviroc C(max) and AUC values were at least twice as high in subjects with ESRD compared with healthy subjects, or if warranted by other safety and tolerability observations.

resultsTwelve subjects (six with ESRD, six healthy) completed the study. When vicriviroc was administered alone, the mean vicriviroc C(max) and AUC ratio estimates (90% CI) for subjects with ESRD versus healthy subjects were 74% (53, 103) and 84% (49, 145), respectively. When ritonavir was added to the regimen, the ratio estimates (90% CI) were 81% (59, 111) and 134% (105, 171), respectively. Ritonavir plasma concentrations were substantially higher in subjects with ESRD than in healthy subjects. Treatment-emergent adverse events considered possibly or probably related to treatment occurred only during the ritonavir period of the study and in one healthy subject and two subjects with ESRD; all were of mild or moderate severity.

conclusionsESRD had no clinically relevant impact on exposure of vicriviroc when vicriviroc was administered alone or in the presence of ritonavir. In this single-dose study, vicriviroc was well tolerated both by healthy subjects and by those with ESRD. Dose adjustment of vicriviroc is therefore not necessary in renally impaired populations.