Human and nonclinical disposition of [<sup>14</sup>C]bictegravir, a potent integrase strand-transfer inhibitor for the treatment of HIV-1 infection
Creators: name: Subramanian, Raju
name: Ling, John
name: Wang, Jianhong
name: Wang, Kelly
name: Hao, Jia
name: Jin, Haolun
name: Lai, Yurong
name: Murray, Bernard
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: Cancer
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: 60506 Virology
subject: FOS: Biological sciences
subject: Computational Biology

description: 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 absorption, metabolism, distribution, and elimination (ADME) characteristics of BIC were determined through <i>in vivo</i> nonclinical and clinical studies (IND 121318).[<sup>14</sup>C]BIC was rapidly absorbed orally in mice, rats, monkeys and human. The cumulative dose recovery was high in nonclinical species (&gt;80%) and humans (95.3%), with most of the excreted dose recovered in faeces. Quantifiable radioactivity with declining concentration was observed in rat tissues suggesting reversible binding. Unchanged BIC was the most abundant circulating component in all species along with two notable metabolites M20 (a sulphate conjugate of hydroxylated BIC) and M15 (a glucuronide conjugate of BIC). BIC was primarily eliminated by hepatic metabolism followed by excretion of the biotransformed products into faeces. <i>In vitro</i> drug-drug interaction (DDI) studies with M15 and M20 demonstrated that no clinically relevant interactions were expected.Overall, BIC is a novel and potent INSTI with a favourable resistance, PK, and ADME profile that provides important improvements over other currently available INSTIs for the treatment of HIV-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 absorption, metabolism, distribution, and elimination (ADME) characteristics of BIC were determined through <i>in vivo</i> nonclinical and clinical studies (IND 121318). [<sup>14</sup>C]BIC was rapidly absorbed orally in mice, rats, monkeys and human. The cumulative dose recovery was high in nonclinical species (&gt;80%) and humans (95.3%), with most of the excreted dose recovered in faeces. Quantifiable radioactivity with declining concentration was observed in rat tissues suggesting reversible binding. Unchanged BIC was the most abundant circulating component in all species along with two notable metabolites M20 (a sulphate conjugate of hydroxylated BIC) and M15 (a glucuronide conjugate of BIC). BIC was primarily eliminated by hepatic metabolism followed by excretion of the biotransformed products into faeces. <i>In vitro</i> drug-drug interaction (DDI) studies with M15 and M20 demonstrated that no clinically relevant interactions were expected. Overall, BIC is a novel and potent INSTI with a favourable resistance, PK, and ADME profile that provides important improvements over other currently available INSTIs for the treatment of HIV-1.