title: Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites.
abstract: Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (∼66% of the administered dose). ∼33% of the administered dose was recovered as the parent drug and its nitro reduction metabolite M30 [2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-amino-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. Unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the α-carbon of piperazine ring; 4-[(10aR,11aS)-7-(4-chlorophenyl)-9,9-dimethyl-1,3,4,6,8,10,10a,11a-octahydropyrazino[2,1-b][1,3]benzoxazin-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) was identified as a major metabolite, representing 12% of total drug-related material. M27 was primarily formed by cytochrome P450 isoform 3A4 (CYP3A4). Steady-state plasma concentrations of M27 in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacologic activities.
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.) hong.liu@abbvie.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Michmerhuizen
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Lao
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Katty
authors.initials: K
authors.lastname: Wan
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Ahmed Hamed
authors.initials: AH
authors.lastname: Salem
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: James
authors.initials: J
authors.lastname: Sawicki
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Michael
authors.initials: M
authors.lastname: Serby
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Srirajan
authors.initials: S
authors.lastname: Vaidyanathan
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Shekman L
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Suresh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Martin
authors.initials: M
authors.lastname: Dunbar
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Jens
authors.initials: J
authors.lastname: Sydor
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Sonia M
authors.initials: SM
authors.lastname: de Morais
authors.affiliation: Bioanalysis and Biotransformation, (H.L., M.J.M., K.W., J.S., M.S., J.S., S.M.M., A.J.L.), Process Chemistry (S.V.), and Clinical Pharmacology and Pharmacometrics (A.H.S., S.L.W., S.A., M.D.), Research & Development, AbbVie, North Chicago, Illinois; Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (A.H.S.); Eli Lilly and Company, Indianapolis, Indiana (Y.L.).
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lee
mesh_terms: D065567:Absorption, Physiological; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax