Evaluation of species difference in peripheral lymphocyte reduction effect by CS ‐0777, a sphingosine 1‐phosphate receptor modulator, based on a pharmacokinetic/pharmacodynamic model analysis

Abstract The 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. M1, the phosphorylated active metabolite of CS‐0777, is a selective sphingosine 1‐phosphate receptor‐1 modulator. A linear one‐and two‐compartment model with 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 via an indirect response model in all animals examined. An Imax of 0.815 and an IC50 of 6.58 ng/ml in healthy rats, an Imax of 0.807 and an IC50 of 5.09 ng/ml in the EAE rats, an Imax of 0.789 and an IC50 of 0.484 ng/ml in monkeys were estimated by indirect PD model. Since the IC50 values calculated in terms of an unbound plasma concentration‐basis in rats and monkeys were within the similar range by correcting the IC50 in blood described above with blood to plasma concentration ratio and plasma free fraction of M1 in each animal, it is considered that the intrinsic activity of M1 against lymphocyte reduction exhibits no species difference. The sensitivity of the lymphocytes against M1 was not affected by the status of EAE. The comparison of the simulated lymphocyte reduction in EAE rats by multiple dosing of CS‐0777 and actual EA...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research