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PHARMACOKINETICS

Single- and Multiple-Dose Pharmacokinetics of Levovirin Valinate Hydrochloride (R1518) in Healthy Volunteers

Yue Huang, PhD, Susanne Ostrowitzki, MD, PhD, George Hill, MD, PhD, Mercidita Navarro, PhD, Nancy Berger, RN, BSN, Paul Kopeck, MS, Cheng I. Mau, BS, Tom Alfredson, PhD and Ritu Lal, PhD

From Clinical Pharmacology (Dr Huang, Dr Lal), Clinical Science (Dr Ostrowitzki, Dr Hill), Biostatistics (Dr Navarro), Clinical Operations (Ms Berger), Regulatory Affairs (Mr Kopeck), Pharma Development Pharmacokinetics and Drug Metabolism (Dr Mau), and Pharmaceutics (Dr Alfredson), Pharma Research, Roche Palo Alto LLC, Palo Alto, California.

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 T1/2 ranging from 6 to 8 hours. The T1/2 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.

Key Words: Levovirin • pharmacokinetics • prodrug • HCV, valine

Address for reprints: Yue Huang, PhD, Clinical Pharmacology, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304.


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