TY - JOUR
T1 - Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection
AU - Agarwal, Kosh
AU - Fung, Scott K.
AU - Nguyen, Tuan T.
AU - Cheng, Wendy
AU - Sicard, Eric
AU - Ryder, Stephen D.
AU - Flaherty, John F.
AU - Lawson, Eileen
AU - Zhao, Sally
AU - Subramanian, G. Mani
AU - McHutchison, John G.
AU - Gane, Edward J.
AU - Foster, Graham R.
N1 - Funding Information:
Dr K Agarwal reports receiving consultancy fees from AbbVie, Astellas, Achillion, BMS, BI, Gilead, GSK, Janssen, Merck, Roche and Novartis, and research/ grant support from BMS and Gilead Sciences.
Publisher Copyright:
© 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
KW - Antiviral
KW - Clinical Trial
KW - Treatment
KW - Viral hepatitis
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UR - http://www.scopus.com/inward/citedby.url?scp=84922840729&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2014.10.035
DO - 10.1016/j.jhep.2014.10.035
M3 - Article
C2 - 25450717
AN - SCOPUS:84922840729
SN - 0168-8278
VL - 62
SP - 533
EP - 540
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -