de diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2' O glucuronide (~4% of dose). No other metabolites were identifiable.
Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for > 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised to tenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target cells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide is hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In human clinical studies, a 25 mg oral dose of tenofovir alafenamide resulted in tenofovir diphosphate concentrations > 4-fold higher in PBMCs and > 90% lower concentrations of tenofovir in plasma as compared to a 300 mg oral dose of tenofovir disoproxil fumarate.
Elimination
Bictegravir is primarily eliminated by hepatic metabolism. Renal excretion of intact bictegravir is a minor pathway (~1% of dose). The plasma bictegravir half-life was 17.3 hours.
Emtricitabine is primarily excreted by the kidneys by both glomerular filtration and active tubular secretion. The plasma emtricitabine half-life was approximately 10 hours.
Tenofovir alafenamide is 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 eliminated by the kidneys by both glomerular filtration and active tubular secretion. Renal excretion of intact tenofovir alafenamide is a minor pathway with less than 1% of the dose eliminated in urine.
Linearity
The multiple dose pharmacokinetics of bictegravir are dose proportional over the dose range of 25 to 100 mg. The multiple dose pharmacokinetics of emtricitabine are dose proportional over the dose range of 25 to 200 mg. Tenofovir alafenamide exposures are dose proportional over the dose range of 8 mg to 125 mg.
Other special populations
Renal impairment
No clinically relevant differences in bictegravir, tenofovir alafenamide, or tenofovir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment (estimated CrCl < 30 mL/min). There are no pharmacokinetic data on bictegravir or tenofovir alafenamide in patients with creatinine clearance less than 15 mL/min. Mean systemic emtricitabine exposure was higher in patients with severe renal impairment (CrCl < 30 mL/min) (33.7 µg•h/mL) than in subjects with normal renal function (11.8 µg•h/mL).
Hepatic impairment
Clinically relevant changes in the pharmacokinetics of bictegravir were not observed in subjects with moderate hepatic impairment. The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited. Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild, moderate, or severe hepatic impairment.
Age, gender and race
Pharmacokinetics of bictegravir, emtricitabine, and tenofovir have not been fully eva luated in the elderly (≥ 65 years of age). Population analyses using pooled pharmacokinetic data from adult trials did not identify any clinically relevant diff |
