title: Single-dose pharmacokinetics of the HCV polymerase inhibitor mericitabine in healthy Caucasian and Japanese subjects.
abstract: To investigate the pharmacokinetics of mericitabine in healthy Caucasian and Japanese subjects, healthy Caucasian (n = 32) and Japanese (n = 32) subjects were randomized to receive single 500, 1,000, or 2,000 mg doses of mericitabine or a placebo, after which plasma and urine samples were collected for 72 h. Mericitabine (prodrug), RO4995855 (parent), and RO5012433 (uridine metabolite) concentrations were quantified by tandem mass spectrometry. Pharmacokinetics were estimated by non-compartmental methods, and pharmacokinetic parameters of RO4995855 were normalized by body weight. Exposure to RO4995855 was similar in both populations after administration of mericitabine 500, 1,000, and 2,000 mg. Mean AUCinf of RO4995855 increased in a dose-proportional manner from 28.8 to 52.3, and 113.0 µg·h/mL in Caucasian subjects, and from 32.5 to 57.1 and 119 µg·h/mL in Japanese subjects. A linear relationship was observed between the weight-adjusted dose of mericitabine and Cmax (r(2) = 0.83 and 0.80) and AUC (r(2) = 0.94 and 0.74) for RO4995855 in Caucasian and Japanese subjects, respectively. Mean half-life and renal clearance of RO4995855 were similar and independent of dose in both populations. The results support the use of the same dosing regimens in Caucasian and Asian subjects.
authors.affiliation: Genentech.
authors.forename: Carla
authors.initials: C
authors.lastname: Washington
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moreira
authors.forename: Joshua
authors.initials: J
authors.lastname: Haznedar
authors.forename: Petra
authors.initials: P
authors.lastname: Goelzer
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Chen
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D044466:Asian People; D001711:Biotransformation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D004311:Double-Blind Method; D054796:Drug Dosage Calculations; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D053719:Tandem Mass Spectrometry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D044465:White People; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003841:Deoxycytidine; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase