Use of an Extensively Humanised 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 firstline treatment for hospitalised COVID-19 patients requiring oxygen. Current British National Formularyprescribing advice warns of a “severe theoretical” or “severe anecdotal” risk of drug-drug interactionsbetween dexamethasone and 138 different medications (Joint Formulary Committee, 2024). 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 which affectconcomitant therapy and dexamethasone efficacy in the treatment of COVID-19, we used a uniquemouse model humanised for cytochrome P450s and the transcription factors which regulate theirexpression, the pregnane X receptor and the constitutive androstane receptor. We found that inductionof CYP3A4 with the anti-cancer drug dabrafenib or the herbal medicine St John’s Wort profoundlyreduced dexamethasone exposure. These data suggest that co-medications which induce cytochromeP450 expression can have a marked effect on dexamethasone exposure and, potentially, clinicalefficacy. We also observed that, rather than increasing CYP3A4 expression, dexamethasone at dosesequivalent to or higher than those used in the treatment of COVID-19 reduced CYP3A4 expressionand increased exposure to dabrafenib. These data indicate the need for a clinical trial to establish therisk of over-exposure to comedications during dexamethasone treatment, including the treatment ofCOVID-19.