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Antimicrobial Agents and Chemotherapy, May 2009, p. 1779-1785, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01290-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of LB80331 and LB80317 following Oral Administration of LB80380, a New Antiviral Agent for Chronic Hepatitis B (CHB), in Healthy Adult Subjects, CHB Patients, and Mice{triangledown}

Man-Fung Yuen,1* Sung-Hack Lee,2 Hyang-Mi Kang,3 Chung Ryeol Kim,3 John Kim,3,{dagger} Vincent Ngai,1 and Ching-Lung Lai1

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong,1 Drug Metabolism and Pharmacokinetics Department, LG Life Sciences R&D, Daejeon, South Korea,2 Clinical Development Department, LG Life Sciences, Seoul, South Korea3

Received 26 September 2008/ Returned for modification 9 December 2008/ Accepted 31 January 2009

LB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (Tmax) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the mean Tmax of LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption.

* Corresponding author. Mailing address: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. Phone: 852 28553984. Fax: 852 28725828, E-mail: mfyuen{at}hkucc.hku.hk

{triangledown} Published ahead of print on 17 February 2009.

{dagger} Present address: College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.

Antimicrobial Agents and Chemotherapy, May 2009, p. 1779-1785, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01290-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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