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

• Published in: Journal of hepatology Vol. 62; no. 3; pp. 533 - 540
• Main Authors: Agarwal, Kosh, Fung, Scott K., Nguyen, Tuan T., Cheng, Wendy, Sicard, Eric, Ryder, Stephen D., Flaherty, John F., Lawson, Eileen, Zhao, Sally, Subramanian, G. Mani, McHutchison, John G., Gane, Edward J., Foster, Graham R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2015
• Subjects: Adenine - adverse effects; Adenine - analogs & derivatives; Adenine - pharmacokinetics; Adenine - therapeutic use; Adult; Antiviral; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Clinical Trial; DNA, Viral - blood; Female; Gastroenterology and Hepatology; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - metabolism; Hepatitis B, Chronic - virology; Humans; Male; Middle Aged; Tenofovir - adverse effects; Tenofovir - pharmacokinetics; Tenofovir - therapeutic use; Time Factors; Treatment; Treatment Outcome; Viral hepatitis; Young Adult; CLcr; ALT; AUCinf; TFV-DP; Viral hepatitis; TDF; DAVGx; BMD; Antiviral; HDV; CKD-EPI; eGFR; Cmax; AST; Clinical Trial; TFV; HBeAg; HBsAg; PBMC; bsAP; Treatment; HIV; AUC0–last; t; Tmax; TAF; HCV; CHB; AUC 0–last; area under the concentration-time curve from time of dosing (0 h) to the last time point with measurable plasma concentration prior to next dose; tenofovir; maximum observed plasma concentration; alanine aminotransferase; bone mineral density; AUC inf; chronic hepatitis B; time to maximum observed plasma concentration; creatinine clearance; T max; human immunodeficiency virus; tenofovir diphosphate; estimated glomerular filtration rate; C max; disease epidemiology collaboration; hepatitis B e antigen; bone-specific alkaline phosphatase; CL cr; hepatitis C virus; tenofovir alafenamide; time-weighted average change in HBV DNA from baseline through Week X; peripheral blood mononuclear cells; hepatitis B surface antigen; tenofovir disoproxil fumarate; AUC from time of dosing (0 h) extrapolated to infinity; aspartate aminotransferase; hepatitis D virus; terminal elimination half-life of the drug in plasma
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2014.10.035

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. Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120mg, or tenofovir disoproxil fumarate 300mg for 28days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4weeks. 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 6.0log10IU/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 −2.76log10IU/ml for the 8, 25, 40, and 120mg groups, respectively) which were also comparable to the control (−2.68log10IU/ml for tenofovir disoproxil fumarate 300mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses ⩽25mg were associated with ⩾92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300mg. Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25mg has been selected for further hepatitis B clinical development.