Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator in development for the treatment of relapsing multiple sclerosis. A population PK (PopPK) model was previously developed from data of healthy volunteers (HV) and MS patients. Pharmacokinetic-pharmacodynamic (PK-PD) models describing the effect of PON on lymphocyte count (LC) and heart rate (HR) were also available based on data from HV.
To evaluate previously developed PopPK and PK-PD models to characterize the effect of PON on LC and HR in patients with MS from a phase 2 study.
Patients randomized (1:1:1:1) in the multicenter, double-blind, B201 study (NCT01006265) received PON 10, 20, and 40 mg QD (up-titrated every 7 days from 10 mg) or placebo for 24 weeks. PON plasma concentrations, LC, and HR measurements (2508, 3938, and 10336 measurements, respectively) were obtained from 461 patients (107, 114, 119, 121 patients in 10, 20, 40 mg PON, or placebo, respectively). Models were fit to the observations using nonlinear mixed-effects models, using NONMEM 7.3.0 (ICON plc).
PON PK were well described by the available open 2-compartment linear PopPK model. The PK-LC model was characterized by parameters (maximal effect and concentration inhibiting 50% LC of 0.86∙109 L-1 and 43.4 ng/mL, respectively) in agreement with those previously obtained in HV. The model estimated a mean reduction of LC at steady state (CV%) of 50.20% (19.2%), 66.61% (12.2%), and 72.36% (12.6%) for 10, 20, and 40 mg doses, respectively. LC are predicted to return to baseline by 1 week after the end of dosing. No clinically relevant covariates were identified for this model, indicating that covariate-based dose adjustments are not warranted. The maximal effect parameter of the PK-HR model was found to be lower in MS patients (24.7% decrease) compared to HV (44.9%) to accommodate a lower incidence of bradycardia (HR<50bpm). After 2 weeks of treatment with 10 mg, the model indicated full tolerance development. Further increasing the PON dose did not have additional effects on HR. Baseline HR was identified as a significant covariate indicating increased bradycardia in case of low baseline HR. The PK-HR model supported first-dose HR monitoring in patients with baseline HR<55 bpm given PON.
The previously developed PopPK, PK-LC, and PK-HR PON models were able to describe the observed data and corresponding variability in patients with MS, consistently with previous knowledge from HV.