Drug–drug–gene interactions and adverse drug reactions

Abstract

The economic and health burden caused by adverse drug reactions has increased dramatically in the last few years. This is likely to be mediated by increasing polypharmacy, which increases the likelihood for drug-drug interactions. Tools utilized by healthcare practitioners to flag potential adverse drug reactions secondary to drug-drug interactions ignore individual genetic variation, which has the potential to markedly alter the severity of these interactions. To date there have been limited published studies on impact of genetic variation on drug-drug interactions. In this review, we establish a detailed classification for pharmacokinetic drug-drug-gene interactions, and give examples from the literature that support this approach. The increasing availability of real-world drug outcome data linked to genetic bioresources is likely to enable the discovery of previously unrecognized, clinically important drug-drug-gene interactions.

PharmVar GeneFocus: CYP2C19

“…For example, fluconazole, fluoxetine, and fluvoxamine are known inhibitors of CYP2C19, and may phenoconvert individuals with a normal CYP2C19 genotype to intermediate or poor metabolizers, whereas rifampin, efavirenz, and St. John's wort are known inducers. 27,28 Of note, drug interactions are of no consequence for CYP2C19 poor metabolizers who lack enzyme activity. Drug-drug interactions are of particular concern in the elderly as polypharmacy is common in this population.…”

Clinically Relevant Cytochrome P450 3A4 Induction Mechanisms and Drug Screening in Three‐Dimensional Spheroid Cultures of Primary Human Hepatocytes

“…1 Many clinically significant DDIs are related to interference with cytochrome P450 (CYP) enzymes, partly due to drug-drug-gene interactions. 2,3 CYP3A4 inhibition but also induction is of particular importance as this enzyme metabolizes over half of all clinically used small molecule drugs. 4 Addressing the liability of drug candidates to induce CYP3A4 early in drug development is thus necessary to reduce costs and enhance patient safety.…”

Opportunist Coinfections by Nontuberculous Mycobacteria and Fungi in Immunocompromised Patients

“…The regimen was complex including several antifungal drugs over time (intravenous amphotericin B deoxycholate, itraconazole, itraconazole), antiretroviral (tenofovir, lamivudine, efavirenz) and antibacillar drugs (sulfamethoxazole-trimethoprim, clarithromycin, ETB, streptomycin and levofloxacin). The likelihood of drug-drug interaction with occurrence of adverse drug effects increases in such regimens when the patient takes multiple drugs (polypharmacy) [184]. In the case of NTM-fungi coinfection in immunocompromised patients, other factors such as the immune status of the patient, existence of background diseases (e.g., diabetes) and the interaction with other compounds such as anticancer drugs, has to be considered in order to select a successful therapy.…”