Prediction of the impact of CYP2C9 genotypes on the drug-drug interaction potential of siponimod with PBPK modeling: a comprehensive approach for drug label recommendations

We predicted the drug-drug interaction (DDI) potential of siponimod in presence of cytochrome-P450 (CYP)2C9/CYP3A4 inhibitors/inducers in subjects with different CYP2C9 genotypes by physiologically-based-pharmacokinetic (PBPK) modeling. The model was established using in vitro and clinical pharmacokinetic (PK) data and verified by adequately predicting siponimod PK when co-administered with rifampin. With strong and moderate CYP3A4 inhibitors, an increased DDI risk for siponimod was predicted for CYP2C9*3/*3 genotype versus other genotypes (AUC ratio [AUCR]: 3.25–4.42 vs. ≤1.51 for strong; 2.46 vs. 1.14–1.32 for moderate). AUCRs increased with moderate (2.15–2.52) and weak (1.12–1.41) CYP3A4/CYP2C9 inhibitors to the same extent for all genotypes. With strong CYP3A4/moderate CYP2C9 inducers and moderate CYP3A4 inducers, predicted AUCRs were 0.21–0.32 and 0.35–0.71, respectively. This complementary analysis to the clinical PK-DDI studies confirmed the relevant influence of CYP2C9 polymorphism on the DDI behavior of siponimod and represented the basis for the DDI labeling recommendations