Identification of Cytochrome P450-Mediated Drug-Drug Interactions at Risk in Cases of Gene Polymorphisms by Using a Quantitative Prediction Model.

BACKGROUND AND OBJECTIVE: The magnitude of drug-drug interactions mediated by cytochrome P450 (CYP) may depend on the genotype of polymorphic cytochromes. The objective of this study was to identify drug-drug interactions with greater magnitude in CYP variant groups than in extensive metabolizers.

METHODS: The in-vivo mechanistic static model was used to predict the area under the curve ratio of drug-drug interactions. Five cytochromes (CYP3A4/5, 2D6, 2C9, 2C19, 1A2) and five groups of genotypes for each polymorphic cytochrome (CYP2D6, 2C9, 2C19) were considered. The area under the curve ratios were calculated for all combinations and all genotypes for 196 substrates and 96 inhibitors. Among the strongest interactions (area under the curve ratio greater than 5), two levels of gene sensitivity of drug-drug interactions were defined: the intermediate sensitivity, with a three- to five-fold stronger interaction in genotype groups other than in extensive metabolizers, and the high sensitivity, with a more than five-fold stronger interaction than in genotype groups other than extensive metabolizers.

RESULTS: A red list of 104 interactions with a sensitivity greater than 3, involving 13 substrates and 24 interactors was obtained. There were 59 and 45 cases of high and intermediate sensitivity, respectively. The genotypes associated with a high sensitivity were CYP2D6 *3-8 *3-8 (sensitivity up to 24.3) and CYP2C19 *2-3*2-3 (sensitivity up to 37.8).

CONCLUSIONS: A cytochrome polymorphism may lead to major drug-drug interactions in poor metabolizers, while these interactions may not be significant in extensive metabolizers. Among the 104 cases studied, the interaction could be of ca. 30-fold larger magnitude in the worst case. Genotyping of the patient and/or therapeutic drug monitoring of the substrate should be carried out when an association mentioned in the red list is prescribed. The concept of gene sensitivity of drug-drug interactions appears promising for the development of precision medicine.