Use of an extensively humanized mouse model to predict the risk of drug-drug interactions in patients receiving dexamethasone

The corticosteroid dexamethasone, which is used to treat numerous health conditions, remains the first-line treatment for patients hospitalized with COVID-19 requiring oxygen. Current British National Formulary prescribing advice warns of a "severe theoretical" or "severe anecdotal" risk of drug-drug interactions between dexamethasone and 138 different medications. In humans, dexamethasone is eliminated via the cytochrome P450 monooxygenase system, particularly CYP3A4. It is also described as a human cytochrome P450-inducing agent. To establish factors that affect concomitant therapy and dexamethasone efficacy in the treatment of COVID-19, we used a unique mouse model humanized for cytochrome P450s and the transcription factors that regulate their expression, the pregnane X receptor, and the constitutive androstane receptor. We found that induction of CYP3A4 with the anticancer drug dabrafenib or the herbal medicine St John's wort profoundly reduced dexamethasone exposure. These data suggest that comedications that induce cytochrome P450 expression can have a marked effect on dexamethasone exposure and, potentially, clinical efficacy. We also observed that rather than increasing CYP3A4 expression, dexamethasone at doses equivalent to or higher than those used in the treatment of COVID-19 reduced CYP3A4 expression and increased exposure to dabrafenib. These data indicate the need for a clinical trial to establish the risk of overexposure to comedications during dexamethasone treatment, including the treatment of COVID-19. SIGNIFICANCE STATEMENT: Current prescribing advice identifies a potential theoretical risk of severe side effects when dexamethasone, one of the most widely used drugs in clinical practice, is coadministered with many other drugs; it is, however, difficult to define the magnitude of this risk for specific drug combinations. We describe the use of cytochrome P450-humanized 8HUM mice to predict drug-drug interactions in patients on polypharmacy, a means of generating data that could better inform clinicians regarding foreseeable drug-drug interactions involving dexamethasone.