Lamivudine and Adefovir Dipivoxil Fixed Dose Combination
Condition: Hepatitis B, Chronic
MeSH terms: Hepatitis B; Hepatitis B, Chronic
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Lamivudine; Adefovir dipivoxil; Fixed dose combination (Lamivudine and Adefovir dipivoxil)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 100mg tablet; 10mg tablet; 100mg/10mg capsule
Other intervention name(s): Heptodin; Hepsera; FDC
Intervention MeSH terms: Lamivudine; Adefovir; Adefovir dipivoxil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment