title: Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator.
abstract: Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent for autoimmune disorders. The impact of hepatic or renal impairment on the pharmacokinetics, safety and tolerability of ponesimod and its inactive metabolites, ACT-204426 and ACT-338375, was evaluated. Two separate single-centre, open-label studies with 32 (hepatic study) and 24 (renal study) male and female individuals were conducted. Hepatic impairment was based on the Child-Pugh classification, and renal impairment was determined by creatinine clearance using the Cockcroft-Gault equation. Individuals with severe hepatic or renal impairment were to be matched (sex and body mass index) with healthy individuals. All individuals received a single dose of 10 mg ponesimod. For ponesimod, the ratio of geometric means of AUC0-∞ for individuals with severe hepatic impairment versus healthy individuals was 3.07 (90% CI: 2.19, 4.32). For severely renally impaired individuals versus healthy individuals, this ratio was 1.14 (0.82, 1.58). Cmax and tmax values of ponesimod were comparable across all groups in both studies. Exposure to metabolites was increased in individuals with moderate or severe hepatic impairment as compared to healthy individuals. During the course of these studies, there were no clinically relevant abnormalities related to vital signs, 12-lead electrocardiograms and clinical laboratory values. Sixteen adverse events (AEs) were reported, 12 of them of mild intensity. No AEs were considered to be treatment related. Overall, ponesimod was well tolerated. In individuals with renal function impairment, dose adjustment is not warranted, whereas the dose should be reduced in individuals with moderate and severe hepatic impairment.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guérard
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Zwingelstein
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoch
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000328:Adult; D019540:Area Under Curve; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D051437:Renal Insufficiency / Q000150:complications*; D012720:Severity of Illness Index; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D053778:Thiazolidines / Q000493:pharmacokinetics
chemical_list: C000613270:ACT-204426; D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; D053778:Thiazolidines; C550169:ponesimod