Human pharmacokinetics prediction with an in vitro–in vivo correction factor approach and in vitro drug-drug interaction profile of bictegravir, a potent integrase-strand transfer inhibitor component in approved biktarvy^® for the treatment of HIV-1 infection

Abstract

1. Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy^®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The in vitro properties, pharmacokinetics (PK), and drug-drug interaction (DDI) profile of BIC were characterised in vitro and in vivo.

2. BIC is a weakly acidic, ionisable, lipophilic, highly plasma protein-bound BCS class 2 molecule, which makes it difficult to predict human PK using standard methods. Its systemic plasma clearance is low, and the volume of distribution is approximately the volume of extracellular water in nonclinical species. BIC metabolism is predominantly mediated by cytochrome P450 enzyme (CYP) 3A and UDP-glucuronosyltransferase 1A1. BIC shows a low potential to perpetrate clinically meaningful DDIs via known drug metabolising enzymes or transporters.

3. The human PK of BIC was predicted using a combination of bioavailability and volume of distribution scaled from nonclinical species and a modified in vitro-in vivo correlation (IVIVC) correction for clearance. Phase 1 studies in healthy subjects largely bore out the prediction and supported the methods used. The approach presented herein could be useful for other drug molecules where standard projections are not sufficiently accurate.

 

Keywords:

• Bictegravir
• HIV-1
• single-tablet combination regimen
• human pharmacokinetics prediction
• in vitro–in vivo correction factor
• drug-drug interaction potential

Acknowledgements

The authors thank Gene Eisenberg, Jolyn Twelves, and Irene Lepist for their role in select in vitro assays; Mike Matles for select bioanalysis; and Philip Morganelli, Peter Pyun, and Haolun Jin for BIC and reference compound synthesis. The authors thank Agilux Laboratories, Covance Laboratories, and MPI Research for conducting the nonclinical in vivo PK studies. Authors thank Sibylle Wilbert for editorial assistance of this manuscript.

Disclosure statement

All authors are current employees except that BS, GR, HZ, JC, and JW are former employees. Parts of this work were previously presented (Wang J, Lazerwith S, Morganelli P, Pyun H, Jin H, Tang J, Matles M, Mwangi J, Wang K, Eisenberg G, Murray B, Rhodes G, Zhang H, Custodio J. 2017. Prediction of bictegravir human pharmacokinetics from protein binding and in vitro-in vivo correlation. Poster session presented at: 21st North American ISSX Meeting; Sep 24−28; Providence, RI).

Additional information

Funding

This work was supported by Gilead Sciences, Inc.