Lamivudine and Adefovir Dipivoxil Fixed Dose Combination

Overview

This is a phase I study being conducted to support the clinical development program of a FDC product of the nucleoside analogue lamivudine and the nucleotide analogue adefovir dipivoxil. To establish bioequivalence, the exposure of lamivudine and adefovir dipivoxil when administered as the FDC will be compared to that of Heptodin (lamivudine) and Hepsera (adefovir dipivoxil) when administered separately. In this study, the FDC product will contain 100mg lamivudine/10mg adefovir dipivoxil. Total 40 healthy adult subjects will be enrolled. The study will include a screening visit and two treatment sessions. The screening visit will be conducted up to 3 weeks prior to the first dose of Session 1. All subjects will receive Regimen A through B according to the randomization schedule. Eligible subjects will be enrolled in the study and randomized to receive the following treatment regimens in table below in one of the following treatment sequences: AB, or BA. There will be a seven to ten days washout period between each treatment session. Pharmacokinetic sampling for measurement of plasma lamivudine and adefovir dipivoxil concentrations will be conducted over a 48-hour period following the morning administration of study medication in each study session. During this time, all subjects will remain in the unit for pharmacokinetic (PK) sample collection. The total duration (from screening to the end of the study) of each subject's participation will be approximately four weeks.

Chronic hepatitis B (CHB) infection is common, with an estimated global prevalence of more than 400 million people, or approximately 5% of the world's population. Chronic hepatitis B virus (HBV) carriers with evidence of ongoing viral replication are at highest risk for the development of active liver inflammation (i.e., hepatitis B) and progressive liver disease. They are also the major contributor to the spread of HBV infection. The goals of therapy in CHB include suppression of HBV replication, reduction of necroinflammatory processes in the liver, and prevention of progression to serious liver disease or death. The HBV polymerase has an error rate that is intermediate between that of human immunodeficiency virus (HIV) and herpes virus polymerases,; this predicts that patients with CHB infection are likely to exhibit some degree of antiviral resistance to nucleoside or nucleotide monotherapies. Indeed, patients on long-term lamivudine therapy have been found to have HBV variants (YMDD variants) with reduced sensitivity to lamivudine in vitro, and have exhibited variably diminished therapeutic responses. A fixed dose combination (FDC) formulation of lamivudine and adefovir dipivoxil for the treatment of CHB. Lamivudine (Heptodin) an active triphosphate (3TC-TP) incorporating into growing DNA chains results in premature chain termination thereby inhibiting HBV DNA synthesis. Adefovir dipivoxil (Hepsera) is an orally bioavailable pro-drug of adefovir, a nucleotide analog of adenosine monophosphate. It can inhibit both the reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA causing chain termination. A FDC would therefore combine the established benefits of two important anti-HBV antiviral drugs, representing the first combination product for the treatment of CHB. In addition to the enhanced efficacy afforded by combination therapy, the use of a combination product could enhance convenience and compliance and ensure that patients receive the two drugs needed. This study will evaluate the bioequivalence of a FDC containing (lamivudine 100 mg/adefovir dipivoxil 10 mg) compared to Heptodin100 mg and Hepsera 10 mg. This dose was selected as both Heptodin 100 mg and Hepsera 10 mg are approved in the PRC for the treatment of CHB. Based on extensive clinical experience with the use of both drugs either as monotherapy or in combination, it is anticipated that the co-administration of both agents in the FDC formulation will be well-tolerated.