Drug Interactions between cisapride and tocilizumab

MONITOR: Plasma concentrations and effects of drugs that are CYP450 substrates may be altered following the initiation of interleukin (IL) inhibitors, tumor necrosis factor (TNF) blockers, or interferon (IFN) inhibitors in patients with chronic inflammatory diseases. The formation of hepatic CYP450 enzymes may be suppressed during infection and chronic inflammation by increased levels of certain cytokines (e.g., interleukins-1, -6, and -10; tumor necrosis factor alpha; interferons). Immunomodulating therapy that improves inflammation by targeting these cytokines may restore or normalize CYP450 enzyme levels resulting in increased or decreased metabolism of these substrates to active or inactive metabolites. 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, rather than in patients with psoriasis and atopic dermatitis. In vitro studies showed that tocilizumab, an IL-6 inhibitor, has the potential to impact expression of various hepatic microsomal enzymes including CYP450 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. Its effects on CYP450 2C8 or transporters is unknown. In vivo studies with omeprazole (a substrate of CYP450 2C19 and 3A4) and simvastatin (a substrate of CYP450 3A4 and OATP 1B1) showed decreases of up to 28% and 57% in systemic exposure, respectively, one week following a single dose of tocilizumab. Likewise, simvastatin and simvastatin acid exposures decreased by 45% and 36%, respectively, in 17 patients with rheumatoid arthritis one week following a single 200 mg subcutaneous dose of sarilumab, another IL-6 inhibitor. A role for other interleukins such as IL-12, IL-17A, or IL-23 in the regulation of CYP450 enzymes has not been clearly established, and it is not known whether antagonists of these interleukins would similarly affect CYP450 metabolism. For example, in drug interaction studies, the IL-23 antagonists risankizumab and tildrakizumab, and the IL-17A antagonist ixekizumab demonstrated no clinically significant effects on the activity of CYP450 isoenzymes 1A2, 3A, 2C19, 2D6, or 2C9. Similarly, data evaluating this interaction are not available for the TNF blockers certolizumab and etanercept.

MANAGEMENT: Caution is advised when treatments targeting cytokines such as interleukins, tumor necrosis factors, or interferons are prescribed to patients receiving concomitant drugs that are CYP450 substrates, particularly those with narrow therapeutic ranges (e.g., antiarrhythmics, anticonvulsants, immunosuppressants, theophylline) or sensitive substrates where decreases in plasma levels may be significant or undesirable (e.g., oral contraceptives, statins, benzodiazepines, opioids). Clinical and/or laboratory monitoring should be considered 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, TNF blockers, and IFN inhibitors on CYP450 activities may persist for several weeks after stopping therapy. Individual product labeling for these products should be consulted for specific recommendations.