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

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.

• Authors: 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
• Journal: Journal of hepatology (J Hepatol) Vol. 62 Issue 3 Pg. 533-40 (Mar 2015) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 25450717 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2015. Published by Elsevier B.V.

Chemical References

• Antiviral Agents
• DNA, Viral
• Tenofovir
• tenofovir alafenamide
• Adenine
• Alanine

Topics

• Adenine (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Adult
• Alanine
• Antiviral Agents (adverse effects, pharmacokinetics, therapeutic use)
• DNA, Viral (blood)
• Female
• Hepatitis B, Chronic (drug therapy, metabolism, virology)
• Humans
• Male
• Middle Aged
• Tenofovir (adverse effects, pharmacokinetics, therapeutic use)
• Time Factors
• Treatment Outcome
• Young Adult