Human pharmacokinetics prediction with an <i>in vitro</i>–<i>in vivo</i> correction factor approach and <i>in vitro</i> drug-drug interaction profile of bictegravir, a potent integrase-strand transfer inhibitor component in approved biktarvy<sup>®</sup> for the treatment of HIV-1 infection
Creators: name: Subramanian, Raju
name: Wang, Jianhong
name: Murray, Bernard
name: Custodio, Joseph
name: Hao, Jia
name: Lazerwith, Scott
name: Staiger, Kelly MacLennan
name: Mwangi, Judy
name: Sun, Hailing
name: Tang, Jennifer
name: Wang, Kelly
name: Rhodes, Gerry
name: Wijaya, Samantha
name: Zhang, Heather
name: Smith, Bill J.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Medicine
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: Cancer
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: 60506 Virology

description: Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy<sup>®</sup>, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The <i>in vitro</i> properties, pharmacokinetics (PK), and drug-drug interaction (DDI) profile of BIC were characterised <i>in vitro</i> and <i>in vivo</i>.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 <i>via</i> known drug metabolising enzymes or transporters.The human PK of BIC was predicted using a combination of bioavailability and volume of distribution scaled from nonclinical species and a modified <i>in vitro</i>-<i>in vivo</i> 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. Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy<sup>®</sup>, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The <i>in vitro</i> properties, pharmacokinetics (PK), and drug-drug interaction (DDI) profile of BIC were characterised <i>in vitro</i> and <i>in vivo</i>. 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 <i>via</i> known drug metabolising enzymes or transporters. The human PK of BIC was predicted using a combination of bioavailability and volume of distribution scaled from nonclinical species and a modified <i>in vitro</i>-<i>in vivo</i> 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.