Prediction of the Impact of Cytochrome P450 2C9 Genotypes on the Drug-Drug Interaction Potential of Siponimod With Physiologically-Based Pharmacokinetic 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 (PK) modeling. The model was established using in vitro and clinical PK data and verified by adequately predicting siponimod PK when coadministered with rifampin. With strong and moderate CYP3A4 inhibitors, an increased DDI risk for siponimod was predicted for CYP2C9*3/*3 genotype vs. other genotypes area under the curve ratio (AUCR): 3.03-4.20 vs. ≤ 1.49 for strong; 2.42 vs. 1.14-1.30 for moderate. AUCRs increased with moderate (2.13-2.49) and weak (1.12-1.42) 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.

Huth F ，Gardin A ，Umehara K ，He H ... -  《-》

In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics.

Jin Y ，Borell H ，Gardin A ，Ufer M ，Huth F ，Camenisch G ... -  《-》

Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects.

Gardin A ，Ufer M ，Legangneux E ，Rossato G ，Jin Y ，Su Z ，Pal P ，Li W ，Shakeri-Nejad K ... -  《-》

Evaluation of Cytochrome P450 3A4-Mediated Drug-Drug Interaction Potential for Cobimetinib Using Physiologically Based Pharmacokinetic Modeling and Simulation.

Budha NR ，Ji T ，Musib L ，Eppler S ，Dresser M ，Chen Y ，Jin JY ... -  《-》

Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes.

Gardin A ，Shakeri-Nejad K ，Feller A ，Huth F ，Neelakantham S ，Dumitras S ... -  《-》