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 [CLCR] >80 mL/min, n = 10) or stable renal impairment (mild: CLCR 50–80 mL/min, n = 10; moderate: CLCR 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 (Cmax), and area under the concentration-time curve (0–12 h) (AUC0–12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0–12 and Cmax 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 AUC0–12 and Cmax 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.