title: The effect of mild to moderate renal impairment on the pharmacokinetics of the nucleoside analog hepatitis C virus polymerase inhibitor mericitabine.
abstract: 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.
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Haznedar
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moreira
authors.forename: Thomas
authors.initials: T
authors.lastname: Marbury
authors.forename: Richard
authors.initials: R
authors.lastname: Robson
authors.forename: William
authors.initials: W
authors.lastname: Smith
authors.forename: Rohit
authors.initials: R
authors.lastname: Kulkarni
authors.forename: Marie L
authors.initials: ML
authors.lastname: Munson
authors.forename: James A
authors.initials: JA
authors.lastname: Thommes
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lemenuel-Diot
authors.forename: Carla
authors.initials: C
authors.lastname: Washington
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000652:urine; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009705:Nucleosides / Q000493:pharmacokinetics* / Q000652:urine; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; D000998:Antiviral Agents; D009705:Nucleosides; D017361:Viral Nonstructural Proteins; D003841:Deoxycytidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: mericitabine; pharmacokinetics; renal impairment