<scp>PBPK</scp> Modeling and Clinical Data Reveal Reduced Impact of <scp>CYP3A4</scp> and <scp>CYP2C9</scp> Inhibitors on Elimination of Siponimod

ABSTRACT Multiple sclerosis (MS) is a significant cause of neurological disability in young adults. Siponimod, a potent sphingosine‐1‐phosphate (S1P) receptor modulator, is used to treat MS by reducing T‐cell recirculation and central inflammation. The presented work includes clinical data describing the impact of the CYP3A4 inhibitor clarithromycin on siponimod metabolism and the results of updated physiologically based pharmacokinetic (PBPK) modeling. A clinical drug–drug interaction (DDI) study assessed the effect of clarithromycin on siponimod pharmacokinetics in healthy participants with the CYP2C9 *1*3 genotype. Results revealed minimal differences in PK: a 2% increase in C max , an 8% increase in AUC last and a 9% increase in AUC inf , confirming no clinically relevant drug–drug interaction (DDI). The existing siponimod PBPK model was updated using these DDI study data, estimating a CYP3A4 fraction metabolized of 6.4% in the CYP2C9*1*1 genotype. Simulations using the updated PBPK model in the absence and presence of the restricted co‐medication (CYP2C9 and CYP3A perpetrators) were conducted. There was no clinically relevant DDI with moderate and strong CYP3A4 inhibitors across CYP2C9 genotypes with a predicted maximum net AUC increase of 1.33. Co‐administration of fluconazole, a moderate CYP3A4 and CYP2C9 inhibitor, was predicted to result in &lt; 2‐fold net AUC increase, except for the genotype CYP2C9*2*2, where a 2.2‐fold net AUC increase compared to the CYP2C9 wild type without fluconazole co‐treatment was observed. Siponimod C max and AUC were comparable across CYP2C9 genotypes during dose titration in the absence or presence of fluconazole, suggesting no impact on the effectiveness of the dose titration regimen.