Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights.
Mult Scler J Exp Transl Clin
; 7(4): 20552173211049168, 2021 Oct.
Article
en En
| MEDLINE
| ID: mdl-34777855
ABSTRACT
BACKGROUND:
Siponimod (BAF312), a selective S1P1/S1P5 agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P1/S1P5-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells.OBJECTIVE:
Generate preclinical evidence confirming siponimod's CNS penetration and activity.METHODS:
Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using 14C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated 123I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P1 receptor quantification in brain homogenates.RESULTS:
In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (Brain/BloodDER) of 6-7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P1 levels. QWBA distribution analysis in rats indicated that [14C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a brain/bloodDER of â¼6, as in rodents.CONCLUSION:
Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Mult Scler J Exp Transl Clin
Año:
2021
Tipo del documento:
Article
País de afiliación:
Suiza