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This effect disappears with repeated dosing, enabling development of innovative uptitration 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\u2010effect I<jats:sub>max<\/jats:sub>model with estimated maximum reduction of 45%, tolerance development, and circadian variation best described this effect. The pooled data from nine clinical studies enabled characterization of interindividual variability. The model was used to simulate different treatment regimens to compare the effect of high initial doses vs. gradual uptitration with respect to the occurrence of bradycardia. The results indicate a better safety profile when using gradual uptitration. 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