ponimod and its major systemic metabolites M3 and M17 do not show anyclinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once-daily for all investigated CYPenzymes and transporters.
Siponimod as an Object of Interaction
CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative metabolismpathways to overall elimination. Physiologically based PK modeling indicates a differential CYP2C9 genotype-dependentinhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, alarger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated.
Coadministration of Siponimod with CYP2C9 and CYP3A4 Inhibitors
The coadministration of fluconazole (moderate CYP2C9 and CYP3A4 dual inhibitor) 200 mg daily at steady-state and asingle dose of siponimod 4 mg in CYP2C9*1/*1 healthy volunteers led to a 2-fold increase in the AUC of siponimod.
Mean siponimod terminal half-life was increased by 50%. Fluconazole led to a 2- to 4-fold increase in the AUCtau,ss ofsiponimod across different CYP2C9 genotypes, according to in silico eva luation [see Drug Interactions (7.5)].
Coadministration of Siponimod with CYP2C9 and CYP3A4 Inducers
The coadministration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 andmoderate CYP2C9 dual inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively in CY2C9*1/*1subjects. Rifampin and efavirenz (moderate CYP3A4 inducer) reduced the AUCtau,ss of siponimod by up to 78% and up to52%, respectively, across CYP2C9 genotypes, according to in silico eva luation [see Drug Interactions (7.6)].
Oral Contraceptives
The effects of coadministration of siponimod 2 mg and 4 mg (twice the recommended dosage) once daily with amonophasic oral contraceptive (OC) containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were assessed in 24healthy female subjects (18 to 40 years of age; CYP2C9*1/*1 genotype). There were no clinically relevant effects on thePK or PD of the OC. No interaction studies have been performed with OCs containing other progestagens; however, aneffect of siponimod on their exposure is not expected.
12.5 Pharmacogenomics
The CYP2C9 genotype has a significant impact on siponimod metabolism. After a single dose of 0.25 mg siponimod,AUCinf and AUClast was approximately 2- and 4-fold higher in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3genotypes, respectively, while there was only a minor increase of Cmax by 21% and 16%, respectively, compared to
extensive metabolizers (CYP2C9*1/*1). Mean half-life is prolonged in CYP2C9*2/*3 and CYP2C9*3/*3 carriers (51hours and 126 hours, respectively).
An apparent systemic clearance (CL/F) of about 3.11 L/h was estimated in CYP2C9 extensive metabolizer(CYP2C9*1/*1 and CYP2C9*1/*2) MS patients after multiple oral administrations of siponimod. Cl/F is 2.5, 1.9, 1.6, and0.9 L/h in subjects with the CYP2C9*2/*2, CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 genotypes respectively.
The resultant increase in siponimod AUC was approximatively 25, 61, 91, and 285% higher in CYP2C9*2/*2,CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 subjects, respectively, as compared to CYP2C9*1/*1 subjects [seeDosage and Administration (2.1, 2.3) and Contraindications (4)]. As the apparent clearance estimated for CYP2C9*1*2subjects is comparable to that of CYP2C9*1/*1 subj |
