title: Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans.
abstract: 1.  Cabotegravir [(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide] is an HIV-1 integrase inhibitor under development as a tablet for both oral lead-in therapy and long-acting (LA) injectable for intramuscular dosing. 2. Metabolism, pharmacokinetics and excretion were investigated in healthy human subjects who received either a single oral dose (28.2 mg) of [(14)C]cabotegravir in a mass balance study, or LA formulations of unlabeled cabotegravir (200-800 mg), intramuscularly or subcutaneously, in a separate study. Metabolism, distribution and excretion of [(14)C]cabotegravir were also investigated in mice, rats and monkeys. 3. Recovery of radioactivity in humans represented a mean total of 85.3% of the dose, including 26.8% in the urine. The mean apparent terminal phase half-life was similar for both cabotegravir and radioactivity, 39 h compared to 41 h. 4. Following oral, intramuscular and subcutaneous administration, cabotegravir was the major component in plasma and the glucuronic acid conjugate (M1) represented the predominant component in urine. Cabotegravir was present in bile along with its major metabolite (M1). 5. The primary metabolite of [(14)C]cabotegravir in mouse, rat and monkey was the same as that in human. In vitro phenotyping experiments demonstrated that cabotegravir was metabolized by UDP-glucuronosyltransferase (UGT) 1A1 and UGT1A9.
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: Gary David
authors.initials: GD
authors.lastname: Bowers
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: Amanda
authors.initials: A
authors.lastname: Culp
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Reese
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: Glenn
authors.initials: G
authors.lastname: Tabolt
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: Lee
authors.initials: L
authors.lastname: Moss
authors.affiliation: b Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: Phuong
authors.initials: P
authors.lastname: Huynh
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: David
authors.initials: D
authors.lastname: Wagner
authors.affiliation: c Project Clinical Platforms & Sciences, GlaxoSmithKline, Research Triangle Park , NC , USA , and.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ford
authors.affiliation: c Project Clinical Platforms & Sciences, GlaxoSmithKline, Research Triangle Park , NC , USA , and.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Gould
authors.affiliation: d Product Development, GlaxoSmithKline, Upper Providence , PA , USA.
authors.forename: Rennan
authors.initials: R
authors.lastname: Pan
authors.affiliation: c Project Clinical Platforms & Sciences, GlaxoSmithKline, Research Triangle Park , NC , USA , and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.affiliation: b Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: David A
authors.initials: DA
authors.lastname: Margolis
authors.affiliation: b Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park , NC , USA .
authors.forename: William R
authors.initials: WR
authors.lastname: Spreen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D020723:Glucuronic Acid / Q000652:urine; D014453:Glucuronosyltransferase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; D054659:Diketopiperazines
chemical_list: D020723:Glucuronic Acid; D014453:Glucuronosyltransferase; D019428:HIV Integrase Inhibitors; D011728:Pyridones; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C000715592:Ugt1a9 protein, mouse; C584914:cabotegravir; D054659:Diketopiperazines
keywords: HIV-1; integrase inhibitor; long-acting injectable; nanosuspension