Bictegravir (BIC) is an investigational, once-daily, unboosted HIV integrase strand transfer inhibitor (INSTI) with potent in vitro activity against most INSTI-resistant variants. BIC is currently in development as a single tablet regimen (STR) coformulated with FTC/TAF for treatment of HIV-1 infection in adults and adolescents. Clinical pharmacology assessments of the PK, ADME and DDI potential were performed.
A single- (SD) and multiple-dose (MD) randomized, double-blind, placebo-controlled (6 active; 2 placebo/cohort) of staggered dose-escalation evaluated SD BIC 5, 25, 50, 100, 300 or 600 mg; or once-daily MD 5, 25, 50, 100 or 300 mg for 14 days (fasted) in healthy volunteers. An ADME/ mass balance study included 8 healthy male subjects dosed with a SD 100 mg plus 100 µCi [14C]-labeled BIC. Blood, urine and feces samples were analyzed for total radioactivity and pooled plasma and excreta samples were radio-profiled. An open-label, six cohort (n=15/cohort), fixed sequence and cross-over study assessed the DDI liability of BIC as a victim through utilization of CYP3A4, UGT1A1, and/or P-gp inhibitors and inducers. Safety was assessed throughout each study.
BIC exposure was dose proportional following SD of 25-100mg. Accumulation at steady-state was approximately 1.6x, consistent with the observed half-life of approximately 18 hours. Following a SD of [14C]-labeled BIC, the total recovery of radioactivity was 95% ± 1.5%, with 60% ± 5.5% from feces and 35% ± 5.0% from urine. Balanced glucuronidation and oxidation contributed to the major clearance pathways of BIC. The DDI study (Table 1) showed increased BIC AUC (61-74%) by CYP3A4 inhibitors voriconazole and DRV/COBI, but showed a greater increase (~4x) by potent dual inhibitors of UGT1A1 and CYP3A4, ATV and ATV+COBI. Coadministration of BIC with a potent CYP3A4/UGT1A1/P gp inducer, rifampin resulted in a 75% decrease of BIC AUC; in contrast, a lesser reduction (38%) was associated with the moderate CYP3A4/P gp inducer, rifabutin. Overall, BIC was well tolerated at all doses studied. No deaths, SAEs, or Grade 3 or 4 AEs were reported. The safety profile for BIC did not differ with increasing doses of SD or MD.
The favorable BIC PK profile supports once daily dosing. The DDI results of BIC are consistent with its ADME profile, in which both CYP3A4 and UGT1A1contributed to BIC elimination. BIC was safe and well tolerated in healthy volunteers.