The utility of pharmacokinetic–pharmacodynamic modeling in the discovery and optimization of selective S1P1 agonists

Abstract

Sphingosine-1-phosphate (S1P1) receptor agonists such as Fingolimod (FTY-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. This class of compound act by inducing peripheral lymphopenia.Using an integrated pharmacokinetic/pharmacodynamic (PK–PD) approach based on an in vivo rat model, novel S1P1 agonists were identified with a predicted more rapid rate of reversibility of lymphocyte reduction in human compared to Fingolimod.The in vivo potency of 15 compounds based on PK–PD modelling of the rat lymphocyte reduction model was correlated with in vitro measures of potency at the S1P1 receptor using β arrestin recruitment and G-protein signalling.A structurally novel S1P1 agonist was identified and predictions of human pharmacokinetics and clinical dose are presented.