title: Cynomolgus monkey as a surrogate for human aldehyde oxidase metabolism of the EGFR inhibitor BIBX1382.
abstract: BIBX1382 was an epidermal growth factor receptor inhibitor under clinical investigation for treatment of cancer. This candidate possessed an attractive preclinical absorption, distribution, metabolism, and excretion profile, yet failed in clinical studies due in part to poor oral exposure, resulting from extensive metabolism by aldehyde oxidase (AO). In vitro metabolism studies were performed in liver cytosol and cryopreserved hepatocytes from multiple species. In addition, a pharmacokinetic study was performed in cynomolgus monkey for comparison with the reported human pharmacokinetics of BIBX1382. Estimated hepatic clearance of BIBX1382 in rhesus (42 ml/min per kg) and cynomolgus monkey (43 ml/min per kg) liver cytosol was comparable to human (≥93% of liver blood flow). Metabolite identification after incubation of BIBX1382 in liver cytosol fortified with the AO inhibitor raloxifene confirmed that AO is involved in the formation of the predominant metabolite (BIBU1476, M1) in cynomolgus monkey. After intravenous and oral administration of BIBX1382 to cynomolgus monkeys, high plasma clearance (118 ml/min per kg) and low oral exposure (C(max) = 12.7 nM and 6% oral bioavailability) was observed, with the exposure of M1 exceeding BIBX1382 after oral dosing. This pharmacokinetic profile compared favorably with the human clinical data of BIBX1382 (plasma clearance 25-55 ml/min per kg and 5% oral bioavailability). Thus, it appears that cynomolgus monkey represents a suitable surrogate for the observed human AO metabolism of BIBX1382. To circumvent clinical failures due to uncharacterized metabolism by AO, in vitro studies in the appropriate subcellular fraction, followed by pharmacokinetic and toxicokinetic studies in the appropriately characterized surrogate species should be conducted for substrates of AO.
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut matt.hutzler@quintiles.com.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Hutzler
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cerny
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Yang
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut.
authors.forename: Constance
authors.initials: C
authors.lastname: Asher
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut.
authors.forename: Diane
authors.initials: D
authors.lastname: Wong
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut.
authors.forename: Kosea
authors.initials: K
authors.lastname: Frederick
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut.
authors.forename: Kyle
authors.initials: K
authors.lastname: Gilpin
mesh_terms: D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009930:Organic Chemicals / Q000097:blood / Q000378:metabolism*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D051381:Rats
chemical_list: C423062:BIBX 1382BS; D009930:Organic Chemicals; D020849:Raloxifene Hydrochloride; D042931:Aldehyde Oxidase; D066246:ErbB Receptors