In:
Biopharmaceutics & Drug Disposition, Wiley, Vol. 37, No. 9 ( 2016-12), p. 561-573
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 I max of 0.815 and an IC 50 of 6.58 nM in healthy rats, an I max of 0.807 and an IC 50 of 5.09 nM in the EAE rats, an I max of 0.789 and an IC 50 of 0.484 nM in monkeys were estimated by the indirect PD model. Since the IC 50 values calculated in terms of the unbound plasma concentration in rats and monkeys were within a similar range, after correction of the IC 50 in 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.
Type of Medium:
Online Resource
ISSN:
0142-2782
,
1099-081X
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
1496395-4
SSG:
12
SSG:
15,3
Permalink