Premium
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
Author(s) -
Huth Felix,
Gardin Anne,
Umehara Kenichi,
He Handan
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1547
Subject(s) - drug , pharmacokinetics , pharmacology , physiologically based pharmacokinetic modelling , drug drug interaction , cyp2c9 , medicine , cytochrome p450 , metabolism
We predicted the drug–drug interaction ( DDI ) potential of siponimod in presence of cytochrome P450 ( CYP )2C9/ CYP 3A4 inhibitors/inducers in subjects with different CYP 2C9 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 CYP 3A4 inhibitors, an increased DDI risk for siponimod was predicted for CYP 2C9*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. AUCR s increased with moderate (2.13–2.49) and weak (1.12–1.42) CYP 3A4/ CYP 2C9 inhibitors to the same extent for all genotypes. With strong CYP 3A4/moderate CYP 2C9 inducers and moderate CYP 3A4 inducers, predicted AUCR s 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 CYP 2C9 polymorphism on the DDI behavior of siponimod and represented the basis for the DDI labeling recommendations.