Population-Based Assessment of Phenoconversion Potential in Switzerland: A Claims Data Study of Key Drug-Metabolizing Enzymes and Transporters.

Purpose: Drug-drug-gene interactions can alter drug exposure and thereby increase the risk of clinically relevant outcomes, such as concentration-dependent toxicity (eg, tacrolimus toxicity in the context of altered CYP3A4/5 activity) or reduced treatment effectiveness. Despite their emerging relevance in clinical research, drug-drug-gene interactions remain understudied and are often ignored in clinical practice. Our objective was to assess the risk of phenoconversion by identifying potential drug-drug-gene interactions involving the transporters OATP1B1 and BCRP and the enzymes CYP2B6 and CYP3A4/5 in the Swiss population. Patients and Methods: Using claims data from the Helsana basic health insurance, we identified all persons of all ages with at least one drug claim between 2017 and 2021 and with Helsana basic health insurance coverage for at least one full year. For the five-year analysis, only persons with insurance for the entire five-year period were included. Within this study population, we assessed and ranked the frequency of potential drug-drug-gene interactions of a pharmacogenetic substrate and an inhibitor/inducer of OATP1B1, BCRP, CYP2B6, or CYP3A4/5. Potential drug-drug-gene interactions were defined as the co-occurrence of a pharmacogenetic substrate and an inhibitor/inducer within a 30- or 5-days window. Results: During the entire five-year period, 18'523 (2.1%) and 12'645 (1.4%) individuals were exposed to potential drug-drug-gene interactions using the 30-day and 5-day windows, respectively. Potential drug-drug-gene interactions most frequently involved CYP3A4/5 (81.0% and 85.3%), followed by CYP2B6 (10.9% and 8.7%) and OATP1B1 (8.7% and 13.3%). The top three drug classes involved were nervous system drugs (75.1%), cardiovascular drugs (10.6%), and dermatologicals (4.0%). Quetiapine ranked first in the number of involved drug pairs, with quetiapine - metamizole being the predominant drug pair. Conclusion: In Switzerland, two out of 100 persons taking drugs metabolized or transported by OATP1B1, BCRP, CYP2B6, and CYP3A4/5 are at potential risk of phenoconversion, predominantly involving CYP3A4/5. These findings quantify real-world phenoconversion potential at the population level and underscore the need for outcome- and genotype-linked studies to determine clinical relevance. As this study was not designed to assess clinical outcomes, future genotype- and outcome-linked investigations are required to determine the actual impact on adverse drug reactions or treatment effectiveness.