Dexamethasone is a dose-dependent perpetrator of drug–drug interactions: implications for use in people living with HIV

Abstract

Global use of dexamethasone in COVID-19 patients has revealed a poor understanding of the drug–drug interaction (DDI) potential of dexamethasone, particularly with antiretroviral agents (ARVs). Dexamethasone is both a substrate and a dose-dependent inducer of cytochrome P450 3A4 (CYP3A4). As many ARVs are substrates and/or inhibitors or inducers of CYP3A4, there is concern about DDIs with dexamethasone either as a perpetrator or a victim. Assessment of DDIs that involve dexamethasone is complex as dexamethasone is used at a range of daily doses (generally 0.5 up to 40 mg) and a treatment course can be short, long, or intermittent. Moreover, DDIs with dexamethasone have been evaluated only for a limited number of drugs. Here, we summarize the available in vitro and in vivo data on the interaction potential of dexamethasone and provide recommendations for the management of DDIs with ARVs, considering various dexamethasone dosages and treatment durations.

Effect of letermovir initiation on tacrolimus concentrations among lung transplant recipients receiving concomitant azole antifungal prophylaxis

“…Patients in this cohort exclusively received immediate‐release FK; therefore, letermovir effects on extended‐release FK exposure could not be analyzed. Additionally, emerging data suggests glucocorticoids may exhibit dose‐dependent CYP3A4 induction, posing some degree of interaction with substrates 16–18 . Similar to previous studies, we did not collect nor analyze steroid doses, though the exclusion of hospital‐admitted patients may have reasonably controlled for this.…”

“…Additionally, emerging data suggests glucocorticoids may exhibit dose-dependent CYP3A4 induction, posing some degree of interaction with substrates. [16][17][18] Similar to previous studies, we did not collect nor analyze steroid doses, though the exclusion of hospital-admitted patients may have reasonably controlled for this.…”

Physiologically Based Pharmacokinetic Modeling Approaches for Patients With SARS‐CoV‐2 Infection: A Case Study With Imatinib

“…Meanwhile, dexamethasone has been reported as a substrate and dose‐dependent inducer of CYP3A, with evidence for interactions with probe drugs of the isoenzymes. 30 Hence, the potential drug interaction between imatinib and dexamethasone was accounted for in the PBPK simulations. Despite only slight improvement of the model predictions (Table 1 ), it is important to account for drug interactions with dexamethasone to increase the mechanistic interpretability and representation of the PBPK model in patients with SARS‐CoV‐2 infection, particularly to predict complex drug interaction scenarios (eg, multiple comedications with CYP3A substrates and/or modulators).…”

“…Despite only slight improvement of the model predictions (Table 1 ), it is important to account for drug interactions with dexamethasone to increase the mechanistic interpretability and representation of the PBPK model in patients with SARS‐CoV‐2 infection, particularly to predict complex drug interaction scenarios (eg, multiple comedications with CYP3A substrates and/or modulators). Importantly, as the extent of in vivo CYP3A induction by dexamethasone varies greatly between CYP3A substrates (victim drugs) and dosing regimens of dexamethasone, 30 the current case study with imatinib may help streamline future endeavors to refine the PBPK modeling approaches in patients with SARS‐CoV‐2 infection.…”

“…This suggests that at steady state, imatinib is more susceptible to induction compared to inhibition of CYP3A enzymes. Meanwhile, dexamethasone has been reported as a substrate and dose‐dependent inducer of CYP3A, with evidence for interactions with probe drugs of the isoenzymes 30 . Hence, the potential drug interaction between imatinib and dexamethasone was accounted for in the PBPK simulations.…”