Single- and multiple-dose pharmacokinetics of levovirin valinate hydrochloride (R1518) in healthy volunteers.
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.
Huang
Yue
Y
Clinical Pharmacology, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Ostrowitzki
Susanne
S
Hill
George
G
Navarro
Mercidita
M
Berger
Nancy
N
Kopeck
Paul
P
Mau
Cheng I
CI
Alfredson
Tom
T
Lal
Ritu
R
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
D000998:Antiviral Agents; D009005:Monosaccharides; D011355:Prodrugs; D014230:Triazoles; C502685:levovirin valinate hydrochloride