title: Population pharmacokinetics of the 5-hydroxymethyl metabolite of tolterodine after administration of fesoterodine sustained release tablet in Western and East Asian populations.
abstract: This analysis was conducted to investigate factors that affect 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics after administration of fesoterodine sustained release tablets to Westerners and East Asians. Ten pharmacokinetic studies and three efficacy/safety studies in overactive bladder (OAB) patients were pooled for the population pharmacokinetic analysis. The plasma 5-HMT concentration data were described by a 1-compartment model with first order absorption and a lag time. Creatinine clearance (CLCR), hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were identified as influential covariates. It was estimated that decreasing of CLCR from 80 to 15 mL/min resulted in a 39.5% reduction in 5-HMT apparent oral clearance (CL/F). Hepatic impairment, CYP2D6 poor metabolizer, and CYP3A inhibitor were estimated to reduce CL/F by about 60%, 40%, and 50%, respectively. CYP3A inducer resulted in about fourfold increase in CL/F. Although sex and Japanese ethnicity were selected as covariates on CL/F, each resulted in only about 10% decrease and increase of CL/F, respectively. Of the influential covariates of 5-HMT CL/F, CLCR, hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were of significance, whereas sex and Japanese ethnicity covariates were considered not to have clinically significant impact on exposures of 5-HMT.
authors.affiliation: Clinical pharmacology, Clinical Research, Development Japan, Pfizer Japan Inc., Tokyo, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Oishi
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Tomono
authors.forename: Hidetomi
authors.initials: H
authors.lastname: Yamagami
authors.forename: Bimal
authors.initials: B
authors.lastname: Malhotra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001559:Benzhydryl Compounds / Q000097:blood* / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood; D003408:Cresols / Q000097:blood*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology; D013607:Tablets; D053201:Urinary Bladder, Overactive / Q000235:genetics / Q000378:metabolism; D064804:Urological Agents / Q000493:pharmacokinetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists; D013607:Tablets; D064804:Urological Agents; C526675:fesoterodine; D003404:Creatinine; D019389:Cytochrome P-450 CYP2D6; D007654:Ketoconazole; D012293:Rifampin
keywords: 5-HMT; drug-drug interaction; ethnic groups; fesoterodine; renal impairment