title: Population pharmacokinetic analysis of a novel muscarinic receptor antagonist, imidafenacin, in healthy volunteers and overactive bladder patients.
abstract: The objectives of this study were to develop a population pharmacokinetic model of imidafenacin and to explore the factors that affect the pharmacokinetics of imidafenecin. A total of 2406 plasma samples were collected from 90 healthy volunteers and 457 patients with overactive bladder. We determined the plasma concentrations of imidafenacin by liquid chromatography with tandem mass spectrometry; resultant data were analyzed by a population approach using NONMEM software. The imidafenacin plasma concentration time course was described using a two-compartment model with first-order absorption and lag time. The robustness of the population pharmacokinetic model was evaluated by bootstrap resampling. The results of the population pharmacokinetic analysis demonstrated that oral clearance was decreased with advancing age, increasing hepatic function parameters (AST and ALP), food intake, and itraconazole coadministration, while the first-order absorption rate constant was decreased with food intake. All parameter estimates from the final model fell within 20% of the bootstrapped mean. In conclusion, we developed a population pharmacokinetic model for imidafenacin that well-described plasma concentration profiles. We also identified the factors affecting imidafenacin pharmacokinetics.
authors.affiliation: Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki, Japan. to.ohno@ono.co.jp
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohno
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakade
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakayama
authors.forename: Junsaku
authors.initials: J
authors.lastname: Kitagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyabe
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Konomi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyata
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011976:Receptors, Muscarinic / Q000378:metabolism*; D053201:Urinary Bladder, Overactive / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007093:Imidazoles; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C120953:imidafenacin