title: Simulation of human plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling.
abstract: 1. The partial glucokinase activator N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319) is biotransformed in humans to N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (M1), accounting for ∼65% of total exposure at steady state. 2. As the disproportionately abundant nature of M1 could not be reliably predicted from in vitro metabolism studies, we evaluated a chimeric mouse model with humanized liver on TK-NOG background for its ability to retrospectively predict human disposition of PF-04937319. Since livers of chimeric mice were enlarged by hyperplasia and contained remnant mouse hepatocytes, hepatic intrinsic clearances normalized for liver weight, metabolite formation and liver to plasma concentration ratios were plotted against the replacement index by human hepatocytes and extrapolated to those in the virtual chimeric mouse with 100% humanized liver. 3. Semi-physiological pharmacokinetic analyses using the above parameters revealed that simulated concentration curves of PF-04937319 and M1 were approximately superimposed with the observed clinical data in humans. 4. Finally, qualitative profiling of circulating metabolites in humanized chimeric mice dosed with PF-04937319 or M1 also revealed the presence of a carbinolamide metabolite, identified in the clinical study as a human-specific metabolite. The case study demonstrates that humanized chimeric mice may be potentially useful in preclinical discovery towards studying disproportionate or human-specific metabolism of drug candidates.
authors.affiliation: a Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Tokyo , Japan.|b Laboratory Animal Research Department , Central Institute for Experimental Animals, Kawasaki , Kanagawa , Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kamimura
authors.affiliation: a Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Tokyo , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: c Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Ibaraki , Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Chijiwa
authors.affiliation: c Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Ibaraki , Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okuzono
authors.affiliation: c Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Ibaraki , Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishiguro
authors.affiliation: c Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Ibaraki , Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: c Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Ibaraki , Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Nishinoaki
authors.affiliation: a Drug Development Solutions Division, Sekisui Medical Co., Ltd. , Tokyo , Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Ninomiya
authors.affiliation: d Showa Pharmaceutical University, Machida , Tokyo , Japan , and.
authors.forename: Marina
authors.initials: M
authors.lastname: Mitsui
authors.affiliation: e Medicinal Sciences, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: d Showa Pharmaceutical University, Machida , Tokyo , Japan , and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: b Laboratory Animal Research Department , Central Institute for Experimental Animals, Kawasaki , Kanagawa , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000097:blood* / Q000493:pharmacokinetics; D002678:Chimera; D005941:Glucokinase / Q000378:metabolism; D022781:Hepatocytes; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010599:Pharmacokinetics; D011743:Pyrimidines / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D001572:Benzofurans; C000598526:N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide; D011743:Pyrimidines; D005941:Glucokinase
keywords: Chimeric mouse; MIST guidance; cytochrome P450; disproportionate metabolite; humanized liver; semi-physiological pharmacokinetics