Ponesimod is a selective sphingosine-1-phosphate-1 (S1P ) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. 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-effect I 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. The model allows studying dosing regimens not clinically tested in silico.

The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A 4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. METHODSTwo double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. RESULTSACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro-and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. CONCLUSIONSFPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2017) 83 476-486 476

These first models for ponesimod on the level of lymphocyte subsets offer a valuable tool for the analysis and interpretation of results from ponesimod trials in autoimmune diseases.

Aims Assessment of time to attain steady state as well as drug accumulation following long‐term treatment with the selective sphingosine‐1‐phosphate 1 receptor modulator cenerimod and prediction of the incidence of low total lymphocyte (LY) counts. Differences in pharmacokinetics and pharmacodynamics based on demographic characteristics and between healthy subjects and systemic lupus erythematosus (SLE) patients were to be identified. Methods Data from 4 Phase I studies and 1 Phase II study were pooled to develop a population pharmacokinetic/pharmacodynamic 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. Conclusion 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.

Introduction Amyloid‐related imaging abnormalities with edema/effusion (ARIA‐E) are commonly observed with anti‐amyloid therapies in Alzheimer's disease. We developed a semi‐mechanistic, in silico model to understand the time course of ARIA‐E and its dose dependency. Methods Dynamic and statistical analyses of data from 112 individuals that experienced ARIA‐E in the open‐label extension of SCarlet RoAD (a study of gantenerumab in participants with prodromal Alzheimer's disease) and Marguerite RoAD (as study of Gantenerumab in participants with mild Alzheimer's disease) studies were used for model building. Gantenerumab pharmacokinetics, local amyloid removal, disturbance and repair of the vascular wall, and ARIA‐E magnitude were represented in the novel vascular wall disturbance (VWD) model of ARIA‐E. Results The modeled individual‐level profiles provided a good representation of the observed pharmacokinetics and time course of ARIA‐E magnitude. ARIA‐E dynamics were shown to depend on the interplay between drug‐mediated amyloid removal and intrinsic vascular repair processes. Discussion Upon further refinement and validation, the VWD model could inform strategies for dosing and ARIA monitoring in individuals with an ARIA‐E history.