Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection

Kosh Agarwal, Scott K. Fung, Tuan T. Nguyen, Wendy Cheng, Eric Sicard, Stephen D. Ryder, John F. Flaherty, Eileen Lawson, Sally Zhao, G. Mani Subramanian, John G. McHutchison, Edward J. Gane, Graham R. Foster

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures. Methods Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. Results 51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses ≤25 mg were associated with ≥92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg. Conclusions Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development.

Original languageEnglish (US)
Pages (from-to)533-540
Number of pages8
JournalJournal of Hepatology
Volume62
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • Antiviral
  • Clinical Trial
  • Treatment
  • Viral hepatitis

ASJC Scopus subject areas

  • Hepatology

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