The effect of mild to moderate renal impairment on the pharmacokinetics of the nucleoside analog hepatitis C virus polymerase inhibitor mericitabine

Clinical Development Phases I-III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open-label study, HCV-negative volunteers (18-75 years) with normal renal function (NRF: creatinine clearance [CL_CR] >80?mL/min, n?=?10) or stable renal impairment (mild: CL_CR 50-80?mL/min, n?=?10; moderate: CL_CR 30-49?mL/min, n?=?10) received oral mericitabine 1000?mg twice daily (BID) (500?mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (C_max), and area under the concentration-time curve (0-12?h) (AUC_0-12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC_0-12 and C_max in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26-1.66) and 1.14 (1.02-1.28), respectively. For moderate renal impairment subjects, the dose-normalized GMR for AUC_0-12 and C_max relative to NRF subjects were 2.51 (90% CI, 2.19-2.88) and 1.76 (1.56-1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment.