Drug Interaction Report

MONITOR: Coadministration with ropeginterferon alfa-2b may increase the plasma concentrations of drugs that are metabolized by CYP450 pathways. The formation of hepatic CYP450 enzymes is down-regulated by increased levels of certain proinflammatory cytokines including interferons, thus treatment with ropeginterferon alfa-2b can effectively suppress CYP450 enzymes resulting in increased exposures of some CYP450 substrates. Clinical data demonstrating the interaction are currently lacking. Ropeginterferon alfa-2b did not inhibit CYP450 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes. However, since interferons may influence CYP450 enzymes via mechanisms that require an extended duration to exert effect (e.g., by modulating transcription factors and altering protein expression and/or structure), enzyme inhibition cannot be evaluated by in vitro assays.

MANAGEMENT: Caution is advised when ropeginterferon alfa-2b is coadministered with drugs that are CYP450 substrates, particularly those with narrow therapeutic ranges (e.g., antiarrhythmics, anticonvulsants, immunosuppressants, theophylline) or sensitive substrates where increases in plasma levels may be significant or undesirable (e.g., statins, benzodiazepines, opioids). Clinical and/or laboratory monitoring should be considered following the initiation or withdrawal of ropeginterferon alfa-2b, and the dosage(s) of the CYP450 substrate(s) adjusted accordingly. Clinicians should note that the effects of interferons on CYP450 activities may persist for several weeks after stopping therapy.

GENERALLY AVOID: In a small, randomized, crossover study, the administration of quinidine with grapefruit juice (compared to water) to healthy volunteers significantly prolonged the time to reach peak plasma quinidine concentrations and decreased the plasma concentrations of its major metabolite, 3-hydroxyquinidine. These changes were associated pharmacodynamically with both a delay and a reduction in the maximal effect on QTc interval. The proposed mechanism is delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits.

MANAGEMENT: Given the drug's narrow therapeutic index, patients receiving quinidine therapy should avoid the consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels.