title: Single- and multiple-dose pharmacokinetics of levovirin valinate hydrochloride (R1518) in healthy volunteers.
abstract: R1518 is a valine ester prodrug of levovirin as an investigational new drug for the treatment of hepatitis C virus. Two phase 1, single- and multiple-dose studies were conducted to investigate the pharmacokinetics of R1518 in healthy volunteers. After oral dosing, R1518 was rapidly and exclusively converted to levovirin. Levovirin plasma concentrations peaked at 2 hours, with T(1/2) ranging from 6 to 8 hours. The T(1/2) of R1518 was less than 1 hour, with relative exposures (R1518/levovirin) less than 6%. A high-fat meal did not affect the pharmacokinetics. The female groups in both studies had higher plasma levels than males did due to age and renal function difference. An accumulation ratio of 1.3 to 1.5 was observed with the twice-daily regimen. About 75% to 90% of the levovirin equivalent dose was recovered in urine. Increase in exposure was slightly disproportionate to increase in dose. Significantly improved oral absorption of levovirin was achieved following administration of R1518.
authors.affiliation: Clinical Pharmacology, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Susanne
authors.initials: S
authors.lastname: Ostrowitzki
authors.forename: George
authors.initials: G
authors.lastname: Hill
authors.forename: Mercidita
authors.initials: M
authors.lastname: Navarro
authors.forename: Nancy
authors.initials: N
authors.lastname: Berger
authors.forename: Paul
authors.initials: P
authors.lastname: Kopeck
authors.forename: Cheng I
authors.initials: CI
authors.lastname: Mau
authors.forename: Tom
authors.initials: T
authors.lastname: Alfredson
authors.forename: Ritu
authors.initials: R
authors.lastname: Lal
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009005:Monosaccharides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011355:Prodrugs / Q000493:pharmacokinetics*; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000998:Antiviral Agents; D009005:Monosaccharides; D011355:Prodrugs; D014230:Triazoles; C502685:levovirin valinate hydrochloride