Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Ponesimod on Heart Rate in Patients with Multiple Sclerosis.

The purpose of this study was to characterize the effect of ponesimod on heart rate (HR) in patients with multiple sclerosis (MS). A previous pharmacokinetic (PK) and pharmacodynamic (PD) model developed in healthy participants was updated using data from Phase 2 and 3 trials conducted in patients with MS. Clinically relevant covariates were assessed. Simulations were conducted to evaluate the impact of the lack of adherence to ponesimod treatment and provide guidance in cases of treatment re-initiation. The maximal effect parameter of the PK/HR model was lower in patients with MS (23.5% decrease) compared to healthy volunteers (43.2%). After 2 weeks of treatment with 10 mg or higher doses, the model indicated full tolerance development. After repeated dosing at 20 mg, tolerance was maintained >60% of the steady-state tolerance for up to 4 days after the last dose. The effect of patient covariates on PK/HR was similar to those identified in healthy participants and not clinically relevant in patients with MS. The population PK/HR model well characterized the effect of ponesimod on the time course of HR in patients with MS. None of the evaluated covariates had a clinically relevant impact. Re-initiating with gradual up-titration is recommended if drug discontinuation lasts ≥4 days. This managed the negative chronotropic effects of ponesimod. No bradycardia events were observed within the first two weeks of treatment in patients with relapsing MS with a baseline HR >55 bpm. This justifies the recommendation included in the label to monitor HR after the first ponesimod dose in these patients.