Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study
| Autor: | Srikanth Neelakantham, Xuemei Tan, Kasra Shakeri-Nejad, Angela Dodman, Eric Legangneux, Sampath Kalluri, Anne Gardin |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Cmax Administration Oral 02 engineering and technology Severity of Illness Index Gastroenterology Young Adult 03 medical and health sciences chemistry.chemical_compound 020210 optoelectronics & photonics 0302 clinical medicine Pharmacokinetics Internal medicine Benzyl Compounds 0202 electrical engineering electronic engineering information engineering Humans Medicine Pharmacology (medical) Renal Insufficiency Adverse effect Aged Pharmacology business.industry Area under the curve Half-life Middle Aged Interim analysis Receptors Lysosphingolipid Siponimod Tolerability chemistry Area Under Curve Azetidines Female business 030217 neurology & neurosurgery Half-Life |
| Zdroj: | Int. Journal of Clinical Pharmacology and Therapeutics. 55:54-65 |
| ISSN: | 0946-1965 |
| DOI: | 10.5414/cp202608 |
| Popis: | To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected inactive metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS).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 vs. HS. All subjects received a single oral dose of siponimod 0.25 mg on day 1; PK and safety were evaluated during the follow-up (~ 13 days).PK of siponimod was marginally affected in severe RI subjects vs. HS: Cmax decreased by 8%, and AUClast and AUCinf increased by 23% and 24%, respectively; half-life (37 vs. 26 hours) and systemic clearance (2.9 vs. 3.4 L/h) were comparable. Siponimod plasma unbound (u) fraction at 4 hours post-dose was similar between the two groups (range: 0.0172 - 0.0550%). Cmax(u) was comparable while AUClast(u) and AUCinf(u) were increased by 33% 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 (RI) compared with matched HS. No adverse events were reported during this study.Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further to severe RI, investigation of PK in subjects with mild and moderate RI was not warranted. . |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|