Siponimod (brand name Mayzent) is a sphingosine-1-phosphate (S1P) receptor modulator used in the treatment and management of relapsing forms of multiple sclerosis (MS) in adults. It works by targeting lymphocytes to decrease the number of circulating cells that are associated with MS symptomatic attacks and disease progression and may also have a direct neuroprotective impact. Siponimod strongly binds to the S1P type 1 and type 5 receptors that are abundantly expressed on lymphocytes and multiple other cell types in the central nervous system (CNS). Off-target interactions and effects on cardiac cells may occur, also. The use of a dose titration schedule is recommended to decrease the risk of bradycardia (see Table 1, Table 2) (1, 2). This medication is approved for multiple forms of relapsing MS (RMS) in the United States (1) and for active, secondary progressive disease in Europe and Canada (2, 3).
Siponimod is metabolized by members of the cytochrome P450 family, specifically CYP2C9 and, to a lesser extent CYP3A4. The CYP2C9 gene is polymorphic and activity scores are used to categorize diplotype into phenotype. Decreased CYP2C9 metabolic activity is associated with increased exposure to siponimod and increased risk of adverse effects. Therefore, individuals with the CYP2C9*3/*3 diplotype (activity score = 0) are contraindicated from taking siponimod (1, 2). Individuals with one copy of the no-function *3 allele (diplotype with activity scores of 0.5 or 1.0) are advised to take half the standard maintenance dose (1, 2). Consideration of genotype and activity score is essential for CYP2C9-based siponimod dosing because labeled dose recommendations are not categorized by phenotype. In the US, there is a modified titration schedule for individuals with a CYP2C9*3 allele (Table 1)(1); however, the European prescribing guidelines do not modify the titration schedule for individuals with a single copy of the CYP2C9*3 allele (heterozygous for CYP2C9*3) (Table 2) (2). The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy similarly recommends a 50% reduced maintenance dosage for intermediate metabolizers (IM) (Table 3) (4). It should be noted that dose recommendations in the Siponimod package label are limited to diplotypes consisting of only CYP2C9 *1,*2, and *3 alleles due to lack of clinical data on the impact of other decreased or no-function alleles(1), while other medication and testing guidelines also consider*5, *6, *8, and *11 (5, 6).