title: Prediction of pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in humans using animal data.
abstract: The pharmacokinetics of CS-023 (RO4908463, formerly R-115685), a novel parenteral carbapenem antibiotic, in humans was successfully predicted using the data collected from mice, rats, rabbits, and dogs; while inclusion of the monkey data led to a significant underestimation of the total plasma clearance (CL). Double logarithmic plots of CL and distribution volume at the steady-state (Vss) vs. body weight in four animal species were linear with high correlation coefficients; and the predicted CL and Vss values in humans agreed well with the observed values after administration of CS-023 by an intravenous drip infusion for 30 min. The plasma concentration-time profile in humans, which was predicted using a bi-exponential equation fitted to a complex Dedrick plot of the animal data, approximated the observed profile. An underestimation of CL caused by including the monkey data in a prediction is quite likely due to the net tubular reabsorption in monkeys, but not at least in rabbits, dogs, and humans.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan. sibaya@sankyo.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Shibayama
authors.forename: Y
authors.initials: Y
authors.lastname: Matsushita
authors.forename: A
authors.initials: A
authors.lastname: Kurihara
authors.forename: T
authors.initials: T
authors.lastname: Hirota
authors.forename: T
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D001835:Body Weight; D015780:Carbapenems / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate
chemical_list: D015780:Carbapenems; C492232:tomopenem