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Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study

Shakeri-Nejad, Kasra and Aslanis, Vassilios and Veldandi, Uday Kiran and Zaehringer, Andreas and Dodman, Angela and Su, Frank and Legangneux, Eric (2016) Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study. Journal of Clinical Pharmacology.

Abstract

This open-label, parallel-group study assessed the pharmacokinetics (PK), safety and tolerability of siponimod and its metabolites (M3 and M5) in subjects with mild, moderate and severe hepatic impairment (HI) compared to demographically-matched healthy subjects (HS). The study enrolled 40 subjects (each HI group, n=8; HS group, n=16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by moderate and severe HI groups. All subjects received a single oral dose of 0.25 mg siponimod on Day 1; PK and safety data were collected during the 21-day follow-up. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2-5 fold increase particularly in the moderate and severe HI groups vs HS. There were no clinically relevant safety findings. These results do not warrant any dose adjustments of siponimod in subjects with HI.

Item Type: Article
Keywords: Pharmacokinetics, Siponimod, Metabolites, Hepatic Impairment, Protein binding
Date Deposited: 23 Sep 2017 00:45
Last Modified: 23 Sep 2017 00:45
URI: https://oak.novartis.com/id/eprint/27448

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