Pharmacokinetic properties of single-dose lamivudine/adefovir dipivoxil fixed-dose combination in healthy Chinese male volunteers

Abstract

Background: Both lamivudine and adefovir dipivoxil are approved for the treatment of chronic hepatitis B (CHB) and have established safety profiles. A fixed-dose combination (FDC) formulation of lamivudine/adefovir dipivoxil for the treatment of CHB may provide dosing convenience and improve adherence.

Objective: This study compared the pharmacokinetic profiles of an FDC capsule containing lamivudine/adefovir dipivoxil 100/10 mg and conventional lamivudine 100-mg + adefovir dipivoxil 10-mg tablets to determine bioequivalence.

Methods: This randomized, open-label, single-dose, 2-period crossover study was conducted in healthy male Chinese subjects. The study included a screening visit, 2 treatment sessions, and a follow-up visit. Subjects who met the inclusion/exclusion criteria were assigned to receive, in randomized order, 1 FDC capsule or 1 tablet each of lamivudine and adefovir dipivoxil. After a 7- to 10-day washout period, alternate treatment was given to the subjects during the second treatment session. Blood samples were collected immediately before and after dosing for 48 hours for plasma drug concentration measurement. Data on adverse events (AEs) were collected from the start of dosing until the follow-up visit. Tolerability assessments included physical examinations with vital sign measurements and clinical laboratory evaluations throughout the study.

Results: Forty subjects were enrolled into the study (mean age, 22.4 years [range, 19-28 years]; weight, 63.8 kg [range, 54-78 kg]). The pharmacokinetic profiles of lamivudine and adefovir were similar between the FDC and reference formulations. The geometric mean ratios (GMRs) for lamivudine C(max) and AUC(0-last) were 1.02 (90% CI, 0.92-1.12) and 0.99 (90% CI, 0.95-1.04), respectively; adefovir, 0.94 (90% CI, 0.89-0.99) and 0.95 (90% CI, 0.91-1.00). A limited number of mild AEs were reported, with no clinically significant changes in vital signs or laboratory results.

Conclusions: The FDC capsule was bioequivalent to the concurrent administration of lamivudine + adefovir dipivoxil tablets based on the 90% CIs of the GMRs for C(max), AUC(0-∞), AUC(0-last), and t12 (all were between 0.80 and 1.25). Both treatments were well-tolerated.

Trial registration: ClinicalTrials.gov NCT01353742.