Abstract

Aims: Assessment of time to attain steady state as well as drug accumulation following long-term treatment with the selective sphingosine-1-phosphate 1 (S1P1 ) receptor modulator cenerimod and prediction of the incidence of low total lymphocyte (LY) counts. Differences in pharmacokinetics (PK) and pharmacodynamics (PD) based on demographic characteristics and between healthy subjects and systemic lupus erythematosus (SLE) patients were to be identified. Methods: Data from four Phase I studies and one Phase II study were pooled to develop a population PK/PD model describing cenerimod concentration and its effect on LY count. Simulations addressed the objectives. Results: Simulations of 365 days of treatment indicated a time to steady state of 49 days and changes in exposure of 15% beyond 35 days. For a dose of 2 mg, the predicted incidences of LY counts below 0.5 and 0.2⋅109 cells/L were 18.2 and 0.6% for healthy subjects and 25.9 and 1.0% for SLE patients, respectively. Incidence increased with higher dose and lower baseline LY counts. For body weights of 50 and 100 kg compared to 75 kg, exposure was predicted to change by +37% and -20%, respectively. Conclusions: Long-term cenerimod administration is not expected to result in exposure and LY count reduction substantially different from results of completed studies. Low LY counts are predicted to occur more frequently in SLE patients compared to healthy subjects. Dose individualization based on the model is not considered necessary. Model-based simulations enable benefit-risk evaluations, supporting planning of late-phase clinical studies and scientific exchange with health authorities.

By Dominik Lott, Pierre-Eric Juif, Jasper Dingemanse, Andreas Krause