Impact of genetic variation on response to therapy
The SmPC for siponimod states that the CYP2C9 genotype was found to influence the clearance (CL/F).
Two population pharmacokinetic analyses indicated that CYP2C9*1/*1 and *1/*2 subjects behave as extensive (normal) metabolisers, *2/*2 and *1/*3 subjects as intermediate metabolisers and *2/*3 and *3/*3 subjects as poor metabolisers. Compared to CYP2C9*1/*1 subjects, individuals with the CYP2C9*2/*2, *1/*3, *2/*3 and *3/*3 genotypes have 20%, 35-38%, 45-48% and 74% smaller CL/F values, respectively. Siponimod exposure is therefore approximately 25%, 61%, 91% and 284% higher in CYP2C9*2/*2, *1/*3, *2/*3 and *3/*3 subjects, respectively, as compared to *1/*1 subjects.
Testing recommendations
The SmPC for siponimod states that before initiation of treatment, patients must be genotyped for CYP2C9 to determine their CYP2C9 metaboliser status.
Therapeutic recommendations
Treatment should be initiated and managed under the supervision of a physician experienced in the management of patients with multiple sclerosis.
Consult the SmPC for detailed information on initiation dose, titration schedule and drug interactions.
CYP2C9 genotype *3/*3 (see note)
- Predictive of significantly higher plasma exposure than normal metabolisers.
- Significantly increased risk of toxicity.
- Siponimod should not be used.
CYP2C9 genotype *2/*3 (see note)
- Predictive of higher plasma exposure than normal metabolisers.
- Initiate with 0.25mg once daily and titrate according to manufacturer’s instructions to a recommended maintenance dose of 1mg once daily.
- There is a potential for drug interactions and the extent of the drug-drug interaction effect is predicted to be dependent on the CYP2C9 genotype. Consult the SmPC.
CYP2C9 genotype *1/*3 (see note)
- Predictive of higher plasma exposure than normal metabolisers.
- Initiate with 0.25mg once daily and titrate according to manufacturer’s instructions to a recommended maintenance dose of 1mg once daily.
- There is a potential for drug interactions and the extent of the drug-drug interaction effect is predicted to be dependent on the CYP2C9 genotype. Consult the SmPC.
All other CYP2C9 genotypes
- Initiate with 0.25mg once daily and titrate according to manufacturer’s instructions to a recommended maintenance dose of 2mg once daily.
- There is a potential for drug interactions and the extent of the drug-drug interaction effect is predicted to be dependent on the CYP2C9 genotype. Consult the SmPC.
Note: In this monograph therapeutic recommendations are provided according to genotype as this reflects the posology and method of administration in the SmPC for siponimod. Users should note that the genotype to phenotype translation methods used in the SmPC for siponimod are different to the standard methodology used by international consortia including the Clinical Pharmacogenomics Implementation Consortium (CPIC®) and may differ from the methods used by reference laboratories. It is recommended to dose siponimod by genotype only.
Further information
The SmPC for siponimod advises that there are other less frequent occurring polymorphisms for CYP2C9 [than those for which dose adjustments have been provided within the SmPC]. The pharmacokinetics of siponimod have not been evaluated in such subjects. Some variant alleles such as *5, *6, *8 and *11 are associated with decreased or loss of enzyme function. It is estimated that CYP2C9 *5, *6, *8 and *11 alleles have a combined frequency of approximately 10% in populations with African ancestry, 2% in Latinos/Hispanics and <0.4% in Caucasians and Asians.
Siponimod is extensively metabolised, mainly by CYP2C9 (79.3%), and to a lesser extent by CYP3A4 (18.5%). However, the CYP2C9 genotype influences the fractional contributions of the two oxidative metabolism pathways to overall elimination. There is a potential for drug interactions with CYP2C9 inhibitors/inducers and CYP3A4 inhibitors/inducers, and the extent of the drug-drug interaction effect is predicted to be dependent on the CYP2C9 genotype. Consult the SmPC for detailed information on drug interactions.
References
Novartis Pharmaceuticals (2024) Mayzent 0.25 mg film-coated tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/11019/smpc (Accessed online 7 May 2025).
