Antiviral efficacy and pharmacokinetics of oral adefovir dipivoxil in chronically woodchuck hepatitis virus-infected woodchucks

The antiviral efficacy of orally administered adefovir dipivoxil was evalua ted in an 18-week study (12 weeks of treatment and 6 weeks of recovery) con ducted with woodchucks chronically infected with woodchuck hepatitis virus (WHV). Adefovir dipivoxil is a prodrug of adefovir designed to enhance its oral bioavailability. Following administration of 15 mg of adefovir dipivox il per kg of body weight in four WHV-infected animals, the mean maximum con centration of adefovir in serum was 0.462 mug/ml, with an elimination half- life of 10.2 h, and the oral bioavailability of adefovir was estimated to b e 22.9% (+/- 11.2%). To study antiviral efficacy, the animals were divided into three groups. There were six animals each in a high-dose group (15 mg/ kglday) and a low-dose group (5 mg/kg/day). A vehicle control group consist ed of five animals because WHV DNA was detectable only by PCR at the time o f the study in one of the original six animals. Efficacy was evaluated by d etermining the levels of WHV DNA in serum. The geometric mean WHV DNA level for the high-dose group diminished by > 40-fold (> 1.6 log(10)) after 2 we eks of treatment and > 300-fold (>2.5 log(10)) at 12 weeks. There was a > 1 0-fold reduction in five of six low-dose animals by 2 weeks, but levels wer e unchanged in one animal. By 12 weeks of treatment there was a > 45-fold ( >1.6 log(10)) reduction of WHV DNA levels, and serum WHV DNA levels were be low the limit of quantification in three of six animals. Viral DNA levels r eturned to pretreatment levels during the 6-week recovery period. There wer e no clinically significant changes in body weight, hematology, or serum ch emistry values, including bicarbonate or lactate, in any of the treated ani mals. No histologic evidence of liver injury was apparent in the biopsies. Under the conditions of this study, adefovir dipivoxil was an effective ant ihepadnaviral agent.