P16 PREDICTION OF BICTEGRAVIR HUMAN PHARMACOKINETICS FROM PROTEIN BINDING AND IN VITRO-IN VIVO CORRELATION

Jianhong Wang , Drug Metabolism, Gilead Sciences, Inc., Foster City, CA
Scott Lazerwith , Medicinal Chemistry, Gilead Sciences, Inc., Foster City, CA
Haolun Jin , Medicinal Chemistry, Gilead Sciences, Inc., Foster City, CA
Philip Morganelli , Medicinal Chemistry, Gilead Sciences, Inc., Foster City, CA
Peter Pyun , Medicinal Chemistry, Gilead Sciences, Inc., Foster City, CA
Jennifer Tang , Pre-Clinical Development, Drug Metabolism, Gilead Sciences, Inc., Foster City, CA
Mike Matles , Drug Metabolism, Gilead Sciences, Inc., Seattle, WA
Judy Mwangi , Drug Metabolism, Gilead Sciences, Inc., Foster City, CA
Kelly Wang , Drug Metabolism, Gilead Sciences, Inc., Foster City, CA
Gene Eisenberg , Drug Metabolism, Gilead Sciences, Inc., Foster City, CA
Bernard P. Murray , Drug Metabolism, Gilead Sciences, Inc., Foster City, CA
Gerry Rhodes , Drug Metabolism, Gilead Sciences, Inc., Foster City, CA
Heather Zhang , Clinical Pharmacology, Gilead Sciences, Inc., Foster City, CA
Joseph Custodio , Clinical Pharmacology, Gilead Sciences, Inc., Foster City, CA
The influence of protein binding is known to effect hepatic clearance of drugs. Bictegravir (BIC) is a novel, potent integrase strand transfer inhibitor (INSTI) with a high in vitro barrier to resistance, and is currently in clinical development for the treatment of HIV-1 infection. This presentation describes the in vitro properties of BIC, a highly protein bound molecule that displayed protein-restricted clearance in nonclinical species, and the in vitro-in vivo extrapolation (IVIVE) approach taken to successfully predict the human pharmacokinetics (PK) of this molecule. The in vitro plasma protein binding of BIC was determined using an equilibrium dialysis method in rat, dog, monkey and human. The in vitro rate of metabolism of BIC was determined in pooled hepatic microsomal fractions from human and nonclinical species in the presence of NADPH and UDPGA. The PK of BIC was determined following intravenous administration in nonclinical species and following oral administration in human. Under conditions achieving equilibrium the unbound fraction of BIC in plasma of rat, dog, monkey and human was 0.01, 1.2, 0.31 and 0.25% and was mainly bound to albumin. The volume of distribution of BIC was 0.09-0.22 L/kg in nonclinical species, suggesting the distribution of BIC was limited to the extracellular compartment. The estimated human Vss was 0.2 L/kg. Different methods were considered for scaling in vitro to in vivo CL but led to over-prediction of in vivo CL across species without consideration of binding, or under-prediction if binding was considered. Calculation of the ratio of the uncorrected in vitro CL to in vivo CL across species revealed a correlation between plasma binding and the fold difference with rat, dog and monkey of 242, 15 and 22, respectively. Since the unbound fraction in plasma between monkey and human was similar, a 25-fold factor was applied to the in vitro CL to estimate an in vivo human CL of 0.007 L/kg. Thus, the projected half-life of BIC in human was estimated to be ~20 h based upon the estimates of clearance and volume of distribution described above. Assuming 50% bioavailability, the human plasma PK was simulated following repeat dosing of BIC 75 mg single agent and the trough concentration at steady state was predicted to be ~2.1 ug/mL. This prediction was confirmed in clinical studies, which showed a BIC half-life of ~18 h with mean trough concentrations of ~3.5 ug/mL at steady state following once daily dosing of BIC 75 mg single agent. BIC is being studied in phase 3 clinical trials in a fixed-dose combination with F/TAF.