rifampin and Urinary-Bladder--Overactive

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.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Benzhydryl Compounds; Creatinine; Cresols; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Delayed-Action Preparations; Female; Genotype; Humans; Ketoconazole; Liver Diseases; Male; Middle Aged; Models, Biological; Muscarinic Antagonists; Rifampin; Tablets; Urinary Bladder, Overactive; Urological Agents; White People; Young Adult

5-Hydroxymethyl tolterodine (5-HMT; the active fesoterodine metabolite) is metabolized via the cytochrome P450 (CYP) 2D6 and CYP3A pathways. Mirabegron is a moderate CYP2D6 inhibitor and weak CYP3A inhibitor. Potential drug-drug interactions (DDIs) following coadministration of these 2 overactive bladder treatments were estimated using physiologically based pharmacokinetic models, developed and verified by comparing predicted and observed pharmacokinetic profiles from clinical studies. Models predicted and verified mirabegron and desipramine (CYP2D6 substrate) and 5-HMT and ketoconazole (strong CYP3A inhibitor) DDIs. Mirabegron model-predicted mean steady-state AUC and C

Topics: Acetanilides; Adult; Benzhydryl Compounds; Cresols; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Humans; Ketoconazole; Male; Middle Aged; Rifampin; Thiazoles; Urinary Bladder, Overactive