Pharmacokinetics, Pharmacodynamics, Tolerability, and Food Effect of Cenerimod, a Selective S1P1 Receptor Modulator in Healthy Subjects

• Published in: International journal of molecular sciences Vol. 18; no. 12; p. 2636
• Main Authors: Juif, Pierre-Eric, Baldoni, Daniela, Reyes, Maribel, Wilbraham, Darren, Febbraro, Salvatore, Vaclavkova, Andrea, Hoch, Matthias, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.12.2017; MDPI
• Subjects: Administration, Oral; Adolescent; Adult; Blood Pressure; Dose-Response Relationship, Drug; Food; Heart Rate; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; Lymphocyte Count; Male; Maximum Tolerated Dose; Middle Aged; Receptors, Lysosphingolipid - agonists; Renal Elimination; S1P1 receptor modulator; pharmacokinetics; food effect; pharmacodynamics; tolerability; lymphocyte
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18122636

The pharmacokinetics, pharmacodynamics, tolerability, and food effect of cenerimod, a potent sphingosine-1-phosphate subtype 1 receptor modulator, were investigated in three sub-studies. Two double-blind, placebo-controlled, randomised studies in healthy male subjects were performed. Cenerimod was administered either as single dose (1, 3, 10 or 25 mg; Study 1) or once daily for 35 days (0.5, 1, 2 or 4 mg; Study 2). A two-period cross-over, open-label study was performed to assess the food effect (1 mg, Study 3). The pharmacokinetic profile of cenerimod was characterised by a tmax of 5.0–6.2 h. Terminal half-life after single and multiple doses ranged from 170 to 199 h and 283 to 539 h, respectively. Food had no relevant effect on the pharmacokinetics of cenerimod. A dose-dependent decrease in lymphocyte count was observed after initiation of cenerimod and reached a plateau (maximum change from baseline: −64%) after 20–23 days of treatment. Lymphocyte counts returned to baseline values at end-of-study examination. One serious adverse event of circulatory collapse (25 mg dose group, maximum tolerated dose: 10 mg) and adverse events of mild-to-moderate intensity were reported. Treatment initiation was associated with transient decreases in heart rate and blood pressure at doses >1 and ≥10 mg, respectively.