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Pharmacokinetics and Safety of Tenofovir Alafenamide in Subjects With Mild or Moderate Hepatic Impairment
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15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19- 21, 2014, Washington, DC
Mark Mascolini
Mild or moderate liver impairment had no clinically relevant impact on concentrations of tenofovir alafenamide (TAF), an investigational tenofovir prodrug for HIV and HBV infection, in a 40-person single-dose study [1]. Results suggest TAF dose adjustment will not be necessary in people with mild to moderate liver impairment.
A tenofovir prodrug being studied as a replacement for tenofovir disoproxil fumarate (TDF), TAF yields lower tenofovir plasma concentrations but higher peripheral blood mononuclear cell concentrations than TDF [2]. As a result, Gilead Sciences researchers developing TAF believe the new prodrug will have a milder side-effect profile than TDF. In a 48-week placebo-controlled double-blind comparison, TAF proved virologically noninferior to tenofovir disoproxil fumarate when each was combined in a single-tablet elvitegravir-based combination for previously untreated people with HIV infection [2].
Researchers enrolled 10 people with mild liver impairment (Child-Pugh-Turcotte classification A, CPT score 5 to 6), 10 people with moderate impairment (CPT B, CPT score 7 to 9), and 20 healthy controls with no liver impairment matched to the impaired group by age, gender, and body mass index. No one had a clinically significant change in liver status within 60 days of screening. All participants took 25 mg of TAF with food after an overnight fast then had intensive pharmacokinetic sampling. The investigators calculated geometric mean ratios (GMR) comparing liver-impaired people with controls and followed US FDA guidance in considering an exposure increase of at least 100% as clinically relevant.
Age averaged about 56 in study participants, with 50% in the mild-impairment group and 70% in the moderate-impairment group men. Body mass index averaged 27.5 kg/m2. All 40 participants completed the study. Treatment-emergent adverse events were mild, considered unrelated to TAF, and similar in incidence in participants with liver impairment and controls. No clinically relevant lab abnormalities emerged in this single-dose study.
Neither mild nor moderate hepatic impairment affected TAF or tenofovir exposure, as indicated by the following GMRs (and 90% confidence intervals) for area under the concentration-time curve (AUC) and maximum concentration (Cmax):
TAF exposure with mild liver impairment:
-- AUClast: GMR 91.8 (65.2 to 129.4)
-- Cmax: GMR 89.0 (57.7 to 137.3)
TAF exposure with moderate liver impairment:
-- AUClast: GMR 115.1 (88.5 to 149.6)
-- Cmax: GMR 118.7 (78.9 to 178.5)
Tenofovir exposure with mild liver impairment:
-- AUClast: GMR 89.3 (67.3 to 118.5)
-- Cmax: GMR 97.0 (75.9 to 124.0)
Tenofovir exposure with moderate liver impairment:
-- AUClast: GMR 95.6 (75.2 to 121.4)
-- Cmax: GMR 87.6 (70.5 to 108.8)
The study revealed no correlations between TAF or tenofovir levels and CPT score or individual lab components of CPT classification (albumin, total bilirubin, prothrombin time, or international normalized ratio). Average free fraction of TAF ranged from 16% to 19% in people with mild impairment and matched controls, and from 14% to 23% in people with moderate impairment and matched controls. Average free fractions of tenofovir exceeded 99% in all groups. These results indicate "a lack of effect of hepatic impairment on TAF or tenofovir protein binding," Gilead investigators said.
"Based on these data," the Gilead team concluded, "no dose adjustment of TAF is necessary in subjects with mild to moderate hepatic impairment." TAF has not been studied in people with severe hepatic impairment.
References
1. Begley R, Martin H, Lawson EB, Wei X, Vimal M, Kearney BP. Pharmacokinetics and safety of tenofovir alafenamide in subjects with mild or moderate hepatic impairment. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 19-21, 2014. Washington, DC. Abstract P_39.
2. Sax P, Brar I, Elion R, et al. 48 Week study of tenofovir alafenamide (TAF) vs. tenofovir disoproxil fumarate (TDF), each in a single tablet regimen with elvitegravir, cobicistat, and emtricitabine for initial HIV treatment. 53rd ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy. September 10-13, 2013. Denver. http://www.natap.org/2013/ICAAC/ICAAC_54.htm
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