Relative bioavailability study of a novel prodrug of tenofovir, tenofovir dipivoxil fumarate, in healthy male fasted volunteers.

BACKGROUND AND OBJECTIVE: Tenofovir dipivoxil fumarate (9-[(R)-2-[[bis (pivaloyloxymethoxy) phosphinoyl] methoxy] propyl] adenine fumarate) is a novel ester prodrug of tenofovir. It has been developed as an anti-hepatitis B virus clinical candidate. The purpose of this study was to determine the pharmacokinetic parameters of tenofovir dipivoxil fumarate (test) and the commercially available tenofovir disoproxil fumarate (Viread®, reference). In addition, the bioavailability of tenofovir dipivoxil fumarate was evaluated in healthy male fasted subjects after a single comparatively equivalent dose.

METHODS: This single-dose, randomized, two-way, open-label, crossover study was conducted at Xijing Hospital, Xi'an, China. The study drug was administered under fasted conditions. Serial blood samples were obtained over 72 hours after oral administration of each treatment. Bioavailability of the drug was assessed in accordance with the State Food and Drug Administration bioequivalence criteria.

RESULTS: Eighteen subjects were enrolled and completed the study, with all study treatments being generally well tolerated. The geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC(last)), and area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) were 124.49% (90% CI 115.85, 133.79), 122.85% (90% CI 115.55, 130.62), and 122.43% (90% CI 115.71, 129.54), respectively.

CONCLUSION: The relative bioavailability of tenofovir dipivoxil was 20% higher compared with tenofovir disoproxil fumarate; this result was consistent with the preclinical data.