title: Evaluation of species difference in peripheral lymphocyte reduction effect of CS-0777, a sphingosine 1-phosphate receptor modulator, based on a pharmacokinetic/pharmacodynamic model analysis.
abstract: Pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS-0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. The phosphorylated active metabolite of CS-0777, M1, is a selective sphingosine 1-phosphate receptor-1 modulator. A linear one- and two-compartment model with a reversible metabolism process characterized the time courses of CS-0777 and M1 concentrations in rats and monkeys, respectively. The relationship between lymphocyte counts and M1 concentrations in blood was well described by an indirect response model in all animals examined. An Imaxof 0.815 and an IC50of 6.58 nM in healthy rats, an Imaxof 0.807 and an IC50of 5.09 nM in the EAE rats, an Imaxof 0.789 and an IC50of 0.484 nM in monkeys were estimated by the indirect PD model. Since the IC50values calculated in terms of the unbound plasma concentration in rats and monkeys were within a similar range, after correction of the IC50in blood described above with the blood to plasma concentration ratio and the plasma free fraction of M1, it was revealed that there is no species difference in the essential activity of M1 against lymphocyte reduction. The sensitivity of the lymphocytes to M1 was not affected by the EAE status. Comparison of the simulated lymphocyte reduction in EAE rats after multiple dosing with CS-0777 and the actual EAE clinical scores implies that the significant suppressive effect on EAE did not require the elimination of all lymphocytes from the blood. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Inaba
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Goto
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tanaka-Takanaka
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Tomisato
authors.affiliation: Oncology Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yuita
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Doi-Komuro
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Ryotaku
authors.initials: R
authors.lastname: Inoue
authors.affiliation: Oncology Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kagari
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000284:Administration, Oral; D000605:Amino Alcohols / Q000008:administration & dosage* / Q000097:blood*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D013045:Species Specificity
chemical_list: D000605:Amino Alcohols; C569297:CS 0777; D011758:Pyrroles; D049349:Receptors, Lysosphingolipid
keywords: pharmacokinetic/pharmacodynamic model analysis; simulation; species difference; sphingosine 1-phosphate receptor modulator