s about 4 hours (range 3-8 hours). Siponimod absorption is extensive (greater than or equal to 70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in feces extrapolated toinfinity). The absolute oral bioavailability of siponimod is approximately 84%. After administration of siponimod 2 mgonce-daily over 10 days, a mean Cmax of 30.4 ng/mL and mean area under plasma concentration-time curve over dosinginterval (AUCtau) of 558 h*ng/mL were observed on day 10. Steady-state was reached after approximately 6 days of oncedailyadministration of siponimod.
Food Effect
Food intake resulted in delayed absorption (the median Tmax increased by approximately 2-3 hours). Food intake had noeffect on the systemic exposure of siponimod (Cmax and AUC). Therefore, MAYZENT may be taken without regard tomeals.
Distribution
Siponimod distributes to body tissues with a moderate mean volume of distribution of 124 L. Siponimod fraction found inplasma is 68% in humans. Animal studies show that siponimod readily crosses the blood-brain-barrier. Protein binding ofsiponimod is greater than 99.9% in healthy subjects and in hepatic and renal impaired patients.
Elimination
Metabolism
Siponimod is extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%). The pharmacologicalactivity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety ofsiponimod in humans.
Excretion
An apparent systemic clearance (CL/F) of 3.11 L/h was estimated in MS patients. The apparent elimination half-life isapproximately 30 hours.
Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion.
Unchanged siponimod was not detected in urine.
Specific Populations
Male and Female Patients
Gender has no influence on siponimod pharmacokinetics (PK).
Racial or Ethnic Groups
The single-dose PK parameters were not different between Japanese and Caucasians healthy subjects, indicating absenceof ethnic sensitivity on the PK of siponimod.
Patients with Renal Impairment
No dose adjustments are needed in patients with renal impairment. Mean siponimod half-life and Cmax (total and unbound)were comparable between subjects with severe renal impairment and healthy subjects. Unbound AUCs were only slightlyincreased (by 33%), compared to healthy subjects, and it is not expected to be clinically significant. The effects of endstagerenal disease or hemodialysis on the PK of siponimod has not been studied. Due to the high plasma protein binding
(greater than 99.9%) of siponimod, hemodialysis is not expected to alter the total and unbound siponimod concentrationand no dose adjustments are anticipated based on these considerations.
Patients with Hepatic Impairment
No dose adjustments for siponimod are needed in patients with hepatic impairment. The unbound siponimod AUCparameters are 15% and 50% higher in subjects with moderate and severe hepatic impairment, respectively, in comparisonwith healthy subjects for the 0.25 mg single dose studied. The increased unbound siponimod AUC in subjects withmoderate and severe hepatic impairment is not expected to be clinically significant. The mean half-life of siponimod wasunchanged in hepatic impairment.
Drug Interaction Studies
Siponimod (and Metabolites M3, M17) as a Causative Agent of InteractionIn vitro investigations indicated that si |
