Gardin, Anne, Dodman, Angela, Kalluri, Sampath, Neelakantham, Srikanth Raju, Legangneux, Eric and Shakeri-Nejad, Kasra (2017) Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study. Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study.

Abstract

Objective
To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS).

Methods
The study enrolled subjects with severe RI (n=8) and matched HS (n=8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects versus HS. All subjects received single oral dose of siponimod 0.25 mg on Day 1; PK and safety were evaluated during the follow-up (~13 days).

Results
PK of siponimod was marginally affected in severe RI subjects versus HS: Cmax decreased by 8% and AUClast and AUCinf increased by 23% and 24%, respectively. Siponimod plasma unbound (u) fraction was 7% higher in the severe RI subjects versus HS. Cmax(u) was comparable while AUClast(u) and AUCinf(u) increased by 32% and 33%, respectively, compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment compared with matched HS. No adverse events were reported during this study.

Conclusions
Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further investigation of PK in subjects with mild and moderate RI was not warranted.

Item Type:	Article
Keywords:	Siponimod, Pharmacokinetics, Metabolites, Renal impairment, Healthy subjects
Date Deposited:	23 Sep 2017 00:45
Last Modified:	23 Sep 2017 00:45
URI:	https://oak.novartis.com/id/eprint/27927