title: Impact of acute fat mobilisation on the pharmacokinetics of the highly fat distributed compound TAK-357, investigated by physiologically based pharmacokinetic (PBPK) modeling and simulation.
abstract: In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2 weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in the case of body weight change was simulated. The PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to a loss of body fat caused the observed concentration increase of TAK-357 in dog plasma. The analysis demonstrates that the disposition of a highly lipophilic and fat-distributed compound can be affected by acute changes in adipose tissue mass. PBPK modeling and simulation proved to be efficient tools for the quantitative hypothesis testing of apparently atypical PK phenomena resulting from acute physiological changes.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Akihiko
authors.identifier: http://orcid.org/0000-0001-6294-4961
authors.initials: A
authors.lastname: Goto
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tagawa
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Yuu
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Sato
authors.affiliation: Drug Safety Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Central Nervous System Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: Inflammation Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants, Leiden, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: DeJongh
authors.affiliation: Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants, Leiden, The Netherlands.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: van Steeg
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Moriwaki
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Asahi
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003198:Computer Simulation; D004285:Dogs; D007192:Indenes / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D008954:Models, Biological; D017207:Rats, Sprague-Dawley
chemical_list: D007192:Indenes; C495910:ramelteon
keywords: PBPK; adipose tissue; body weight; fat mobilisation; lipophilic compound