Chemical formula: C₂₁H₁₈F₃N₃O₅ Molecular mass: 449.386 g/mol PubChem compound: 90311989
Bictegravir is an integrase strand transfer inhibitor (INSTI) that binds to the integrase active site and blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Bictegravir has activity against HIV-1 and HIV-2.
The antiviral activity of bictegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes The 50% effective concentration (EC50) values for bictegravir were in the range of < 0.05 to 6.6 nM. The protein-adjusted EC95 of bictegravir was 361 nM (0.162 micrograms/mL) for wild type HIV-1 virus. Bictegravir displayed antiviral activity in cell culture against HIV-1 group (M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from < 0.05 and 1.71 nM), and activity against HIV-2 (EC50 = 1.1 nM).
HIV-1 isolates with reduced susceptibility to bictegravir have been selected in cell culture. In one selection, amino acid substitutions M50I and R263K emerged and phenotypic susceptibility to bictegravir was reduced 1.3-, 2.2-, and 2.9-fold for M50I, R263K, and M50I+R263K, respectively. In a second selection, amino acid substitutions T66I and S153F emerged and phenotypic susceptibility to bictegravir was shifted 0.4-, 1.9-, and 0.5-fold for T66I, S153F, and T66I+S153F, respectively.
The susceptibility of bictegravir was tested against 64 INSTI-resistant clinical isolates (20 with single substitutions and 44 with 2 or more substitutions). Of these, all single and double mutant isolates lacking Q148H/K/R and 10 of 24 isolates with Q148H/K/R with additional INSTI resistance associated substitutions had ≤ 2.5-fold reduced susceptibility to bictegravir; > 2.5-fold reduced susceptibility to bictegravir was found for 14 of the 24 isolates that contained G140A/C/S and Q148H/R/K substitutions in integrase. Of those, 9 of the 14 isolates had additional mutations at L74M, T97A, or E138A/K. In addition, site-directed mutants with G118R and T97A+G118R had 3.4- and 2.8-fold reduced susceptibility to bictegravir, respectively. The relevance of these in vitro crossresistance data remains to be established in clinical practice.
Bictegravir demonstrated equivalent antiviral activity against 5 NNRTI-resistant, 3 NRTI-resistant, and 4 PI-resistant HIV-1 mutant clones compared with the wild-type strain.
Bictegravir is absorbed following oral administration with peak plasma concentrations occurring at 2.0-4.0 hours after administration of B/F/TAF. Relative to fasting conditions, the administration of B/F/TAF with either a moderate fat (~600 kcal, 27% fat) or high fat meal (~800 kcal, 50% fat) resulted in an increase in bictegravir AUC (24%). This modest change is 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 bictegravir were Cmax = 6.15 mcg/mL (22.9%), AUCtau = 102 mcg•h/mL (26.9%), and Ctrough = 2.61 mcg/mL (35.2%).
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.
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.
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.
The multiple dose pharmacokinetics of bictegravir are dose proportional over the dose range of 25 to 100 mg.
No clinically relevant differences in bictegravir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment (estimated CrCl < 30 mL/min). There are no pharmacokinetic data on bictegravir in patients with creatinine clearance less than 15 mL/min.
Clinically relevant changes in the pharmacokinetics of bictegravir were not observed in subjects with moderate hepatic impairment.
Pharmacokinetics of bictegravir have not been fully evaluated in the elderly (≥ 65 years of age). Population analyses using pooled pharmacokinetic data from adult trials did not identify any clinically relevant differences due to age, gender or race on the exposures of bictegravir.
Bictegravir was not mutagenic or clastogenic in conventional genotoxicity assays.
Bictegravir was not carcinogenic in a 6-month rasH2 transgenic mouse study (at doses of up to 100 mg/kg/day in males and 300 mg/kg/day in females, which resulted in exposures of approximately 15 and 23 times, in males and females, respectively, the exposure in humans at the recommended human dose) nor in a 2-year rat study (at doses of up to 300 mg/kg/day, which resulted in exposures of approximately 31 times the exposure in humans).
Studies of bictegravir in monkeys revealed the liver as the primary target organ of toxicity. Hepatobiliary toxicity was described in a 39-week study at a dosage of 1000 mg/kg/day, which resulted in exposures of approximately 16 times the exposure in humans at the recommended human dose, and was partially reversible after a 4-week recovery period.
Studies in animals with bictegravir have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with bictegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints.
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