Modeling Tolerance Development for the Effect on Heart Rate of the Selective S1P1 Receptor Modulator Ponesimod

Abstract

Ponesimod is a selective sphingosine-1-phosphate-1 (S1P₁) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. This effect disappears with repeated dosing, enabling development of innovative up-titration regimens to optimize patient safety. There are currently no published pharmacokinetic/pharmacodynamic models describing the heart rate reduction of S1P receptor modulators in humans. The model developed here provides quantification of this effect for ponesimod. A direct-effect I_max model with estimated maximum reduction of 45%, tolerance development, and circadian variation best described this effect. The pooled data from 9 clinical studies enabled characterization of inter-individual variability. The model was used to simulate different treatment regimens to compare the effect of high initial doses versus gradual up-titration with respect to the occurrence of bradycardia. Results indicate a better safety profile when using gradual up-titration. The model allows studying dosing regimens not clinically tested in silico.