Tolerance modeling: effects of the selective S1P1 receptor modulator ponesimod on heart rate
Dominik Lott (1,2), Jasper Dingemanse (1), Thorsten Lehr (2), Andreas Krause (1)
(1) Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Modeling and Simulation, Allschwil, Switzerland, (2) Saarland University, Department of Clinical Pharmacy, Saarbrücken, Germany
Objectives: Development of a population pharmacokinetic/pharmacodynamic (PK/PD) model to characterize the effect of the selective S1P1 receptor modulator ponesimod on heart rate (HR), including the development of tolerance upon repeated dosing.
Methods: ECG HR data from 280 subjects in 9 phase 1 studies (42500 measurements in total) were pooled (single doses of up to 75 mg and multiple once-daily doses of up to 100 mg).
The PK/PD model was built sequentially. Based on the PK model (1), PD model selection started with the analysis of placebo data. Presence of a circadian rhythm and placebo effect(s) were investigated. Subsequently, all data were used to include the drug effect and the development of tolerance. With HR as safety parameter, particular focus was placed on adequate capturing of the variability to predict the occurrence of bradycardia (HR < 40 bpm).
Results: A direct-effect Imax model with tolerance compartment and circadian rhythm was found to best describe the effect of ponesimod on HR. Baseline HR was estimated as 67.2 bpm and found to vary with an amplitude of 6.6% during the day. The circadian maximum was estimated to be reached at 5 PM. Although suggested by individual subjects' data, a placebo effect could not be identified. The maximum possible reduction in HR was estimated as 50% (from baseline), decreasing with development of tolerance with multiple doses. The appearance of tolerance was fast (0.41/h) compared to its decrease (0.011/h) indicating rapid onset and sustained maintenance of tolerance, allowing for multiple days of treatment interruption without complete loss of tolerance.
The effect of the first dose of ponesimod on HR including inter-individual variability was simulated using the final model. The median HR (10th to 90th percentile) at the time of maximum decrease was estimated as 59 (50-70), 53 (44-66), 48 (38-62), and 44 (34-59) bpm for doses of 2, 5, 10, and 20 mg, respectively. These results show that the risk of eliciting HR values < 40 bpm is minimal following an initial dose of 2 mg, the dose selected as starting dose for phase 3 clinical development (2-4), followed by gradual up-titration.
Conclusions: This analysis quantifies the effect of ponesimod on HR including the development of tolerance. A large number of measurements from 9 phase 1 studies provide robust data, allowing to simulate up-titration regimens to minimize the risk of bradycardia. In turn, these regimens can be clinically investigated in patients.
References:
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