clinically meaningful and B/F/TAF can be administered with or without food.
Following oral administration of B/F/TAF with or without food in HIV-1 infected adults, the multiple dose mean (CV%) pharmacokinetic parameters of bictegravir were Cmax = 6.15 mcg/mL (22.9%), AUCtau = 102 mcg•h/mL (26.9%), and Ctrough = 2.61 mcg/mL (35.2%).
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1.5-2.0 hours after administration of B/F/TAF. The mean absolute bioavailability of emtricitabine from 200 mg hard capsules was 93%. Emtricitabine systemic exposure was unaffected when emtricitabine was administered with food and B/F/TAF can be administered with or without food.
Following oral administration of B/F/TAF with or without food in HIV-1 infected adults, the multiple dose mean (CV%) pharmacokinetic parameters of emtricitabine were Cmax = 2.13 mcg/mL (34.7%), AUCtau = 12.3 mcg•h/mL (29.2%), and Ctrough = 0.096 mcg/mL (37.4%).
Tenofovir alafenamide is rapidly absorbed following oral administration with peak plasma concentrations occurring at 0.5-2.0 hours after administration of B/F/TAF. Relative to fasting conditions, the administration of tenofovir alafenamide with a moderate fat meal (~600 kcal, 27% fat) and a high fat meal (~800 kcal, 50% fat) resulted in an increase in AUClast by 48% and 63%, respectively. These modest changes are not considered clinically meaningful and B/F/TAF can be administered with or without food.
Following oral administration of B/F/TAF with or without food in HIV-1 infected adults, the multiple dose mean (CV%) pharmacokinetic parameters of tenofovir alafenamide were Cmax = 0.121 mcg/mL (15.4%), and AUCtau = 0.142 mcg•h/mL (17.3%).
Distribution
In vitro binding of bictegravir to human plasma proteins was > 99% (free fraction ~0.25%). The in vitro human blood to plasma bictegravir concentration ratio was 0.64.
In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 mcg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.
In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01-25 mcg/mL. Ex-vivo binding of tenofovir alafenamide to human plasma proteins in samples collected during clinical studies was approximately 80%.
Biotransformation
Metabolism is the major clearance pathway for bictegravir in humans. In vitro phenotyping studies showed that bictegravir is primarily metabolized by CYP3A and UGT1A1. Following a single dose oral administration of [14C]-bictegravir, ~60% of the dose from faeces included unchanged parent, desfluoro-hydroxy- BIC-cysteine-conjugate, and other minor oxidative metabolites. Thirty five percent of the dose was recovered from urine and consisted primarily of the glucuronide of bictegravir and other minor oxidative metabolites and their phase II conjugates. Renal clearance of the unchanged parent was minimal.
Following administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~86%) and faeces (~14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3' sulfoxi |
