Pharmacokinetics, Safety, and Tolerability of Maraviroc in HIV-Negative Subjects with Impaired Renal Function

Purpose: This open-label, nonrandomized, parallel-group study was conducted to explore the pharmacokinetics, safety, and tolerability of maraviroc in renally impaired subjects. Methods: Subjects with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) (n = 6 per group) were enrolled. Subjects with normal function (period 1), severe impairment, and ESRD received a single 300 mg dose of maraviroc. Subjects with normal function (period 2), mild impairment, and moderate impairment received 150 mg for 7 days at adjusted intervals of twice daily, once daily, and every 48 hours, respectively, with saquinavir/ritonavir (SQV/r). Maraviroc was quantified in plasma, urine, and dialysate by tandem high-performance liquid chromatography-mass spectrometry. Results: With SQV/r, geometric mean steady-state maraviroc area under the plasma concentration-time curve for the dosing interval (AUC(tau)) was 5,341 (coefficient of variation [CV], 27%), 8,119 (35%), and 6,193 (27%) h.ng/mL, in normal function, mild, and moderate impairment groups, respectively. Without SQV/r, 2% to 3% of the maraviroc dose was recovered in urine versus 15% to 25% of steady-state dose when given with SQV/r. Moderate to high intersubject variability in exposure was noted. AUC from zero to infinity (AUC(inf)) was similar to historical single-dose data in subjects with ESRD: low in those with normal function, and high in those with severe impairment. Dialysis did not influence maraviroc exposure. Maraviroc was well tolerated. Conclusions: The data suggest that no dosing interval adjustments are required in subjects with renal impairment when maraviroc is administered alone. However, maraviroc dosing interval adjustment is warranted in renally impaired patients receiving potent CYP3A4 inhibitors. Reference to local prescribing information is recommended, because dose recommendations in renally impaired patients may differ between regions.