Pharmacotherapeutic group: Antiviral for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors. ATC code: J05AF13.
Pharmacology: Mechanism of action: Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). Tenofovir alafenamide enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is primarily hydrolyzed to form tenofovir by carboxylesterase 1 in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain termination.
Tenofovir has activity that is specific to hepatitis B virus and human immunodeficiency virus (HIV-1 and HIV-2). Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses.
Antiviral activity: The antiviral activity of tenofovir alafenamide was assessed in HepG2 cells against a panel of HBV clinical isolates representing genotypes A-H. The EC50 (50% effective concentration) values for tenofovir alafenamide ranged from 34.7 to 134.4 nM, with an overall mean EC50 of 86.6 nM. The CC50 (50% cytotoxicity concentration) in HepG2 cells was > 44400 nM.
Resistance: No amino acid substitutions associated with resistance to Tenofovir alafenamide were identified in these isolates (genotypic and phenotypic analyses).
Cross-resistance: The antiviral activity of tenofovir alafenamide was evaluated against a panel of isolates containing nucleos(t)ide reverse transcriptase inhibitor mutations in HepG2 cells. HBV isolates expressing the rtV173L, rtL180M, and rtM204V/I substitutions associated with resistance to lamivudine remained susceptible to tenofovir alafenamide (< 2-fold change in EC50). HBV isolates expressing the rtL180M, rtM204V plus rtT184G, rtS202G, or rtM250V substitutions associated with resistance to entecavir remained susceptible to tenofovir alafenamide. HBV isolates expressing the rtA181T, rtA181V, or rtN236T single substitutions associated with resistance to adefovir remained susceptible to tenofovir alafenamide; however, the HBV isolate expressing rtA181V plus rtN236T exhibited reduced susceptibility to tenofovir alafenamide (3.7-fold change in EC50). The clinical relevance of these substitutions is not known.
Pharmacokinetics: Absorption: Following oral administration of Tenofovir alafenamide under fasted conditions in adult patients with chronic hepatitis B, peak plasma concentrations of tenofovir alafenamide were observed approximately 0.48 hours post-dose. In patients with CHB, mean steady state AUC0-24 for tenofovir alafenamide and tenofovir were 0.22 μg·hr/mL and 0.32 μg·hr/mL, respectively. Steady state Cmax for tenofovir alafenamide and tenofovir were 0.18 and 0.02 μg/mL, respectively. Relative to fasting conditions, the administration of a single dose of Tenofovir alafenamide with a high fat meal resulted in a 65% increase in tenofovir alafenamide exposure.
Distribution: The binding of tenofovir alafenamide to human plasma proteins was approximately 80%. The binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01-25 μg/mL.
Biotransformation: Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for > 80% of an oral dose. It is shown that tenofovir alafenamide is metabolized to tenofovir (major metabolite) by carboxylesterase-1 in hepatocytes; and by cathepsin A in peripheral blood mononuclear cells (PBMCs) and macrophages. Tenofovir alafenamide is hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. Tenofovir alafenamide is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolized by CYP3A4.
Elimination: Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminated in urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofovir alafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively. Tenofovir is renally eliminated from the body by the kidneys by both glomerular filtration and active tubular secretion.
Linearity/non-linearity: Tenofovir alafenamide exposures are dose proportional over the dose range of 8 to 125 mg.
Pharmacokinetics in special populations: Age, gender and ethnicity: No clinically relevant differences in pharmacokinetics according to age or ethnicity have been identified. Differences in pharmacokinetics according to gender were not considered to be clinically relevant.
Hepatic impairment: In patients with severe hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir are lower than those with normal hepatic function. When corrected for protein binding, unbound (free) plasma concentrations of tenofovir alafenamide in severe hepatic impairment and normal hepatic function are similar.
Renal impairment: No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics were observed between healthy subjects and patients with severe renal impairment (estimated CrCl > 15 but < 30 mL/min).
Paediatric population: No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics were observed between adolescent and adult HIV-1-infected subjects.