Drug Interactions between revumenib and rilonacept

MONITOR: Coadministration of interleukin (IL) inhibitors with CYP450 substrates that are also immunosuppressants could result in an alteration of the plasma concentration of the CYP450 substrate and an increased risk of shared side effects, such as infection or myelosuppression. In general, inflammation is associated with an elevation of pro-inflammatory cytokines like IL-1 beta and IL-6, which can bind to receptors present on hepatocytes and affect the expression level of the CYP450 isoenzyme. Agents that target these cytokines may affect the levels of CYP450 isoenzymes and result in altered drug metabolism of their substrates. The therapeutic target and disease state being treated may play a role in the significance of this interaction. The most evidence is currently for agents targeting the actions of IL-6 and in disease states with high levels of inflammation, such as rheumatoid arthritis (RA), rather than in patients with psoriasis and atopic dermatitis. Clinical data are limited, variable, and not available for all agents that reduce cytokine production. Studies involving the IL-6 inhibitors tocilizumab and sarilumab in RA patients showed similar results on the CYP450 3A4 probe, simvastatin, with reductions in the systemic exposure (AUC) of simvastatin and its metabolite (simvastatin acid) of 45% to 57% and 36% to 39%, respectively. Smaller reductions in the AUC of other probe substrates, omeprazole (2C19) and dextromethorphan (2D6), were also observed following treatment with tocilizumab. However, the AUC of CYP450 substrates is not always reduced. A study with brodalumab showed an increase in the AUC of midazolam (3A4) by 24%. Alternatively, some IL inhibitors (e.g., risankizumab and tildrakizumab) have not been shown to affect any CYP450 substrates when evaluated with probe substrates.

MANAGEMENT: Caution may be advisable when IL inhibitors are prescribed to patients receiving concomitant drugs that are both CYP450 substrates and immunosuppressants. Clinical and/or laboratory monitoring may be appropriate following the initiation or withdrawal of such treatments, and the dosage(s) of the CYP450 substrate(s) adjusted accordingly. Clinicians should note that the effects of IL inhibitors on CYP450 activities may persist for several weeks after stopping therapy. Individual product labeling should be consulted for these products. Some manufacturers no longer recommend general precautions with CYP450 substrates due to updated study data indicating no clinically significant changes in the exposure of probe CYP450 substrates. However, CYP450 substrates that are also immunosuppressants may still require additional precautions given a similar adverse effect profile to the IL inhibitor.