Drug Interaction Report

MONITOR: Coadministration of maribavir may increase the plasma concentrations of immunosuppressant drugs that are substrates of CYP450 3A4 and/or P-glycoprotein (P-gp), such as cyclosporine, everolimus, sirolimus, and tacrolimus. The proposed mechanism involves enhanced absorption as well as decreased clearance of the immunosuppressant drugs due to inhibition of both P-gp-mediated drug efflux in the intestine and CYP450 3A4-mediated metabolism in the intestine and liver by maribavir. In a pharmacokinetic study conducted in 25 adult renal transplant patients receiving a stable, twice daily dose of tacrolimus (0.5 to 16 mg/day), mean tacrolimus peak blood concentration (Cmax), systemic exposure (AUC) and trough blood concentration (Cmin, 12 hours post-dose) increased by 38%, 51% and 57%, respectively, in patients coadministered maribavir (400 mg twice daily) versus patients coadministered placebo for 7 days. The interaction was also suspected in a case report of a 59-year-old hospitalized male renal transplant patient treated with maribavir 400 mg twice daily for cytomegalovirus (CMV) viremia. The patient previously achieved target everolimus trough concentrations of 6 to 8 ng/mL while taking a total daily dose of everolimus 3.5 mg, but five days after maribavir initiation the everolimus trough concentration increased to 17.2 ng/mL, necessitating a one-day interruption of everolimus treatment and a dosage reduction to 2.5 mg/day. Similarly, elevated sirolimus levels occurred in a 65-year-old male lung transplant recipient following initiation of maribavir for the treatment of ganciclovir-resistant CMV infection. This patient also required dosage adjustment of sirolimus to maintain therapeutic levels during approximately 6 months of maribavir therapy. According to the prescribing information, immunosuppressant drug level increase was reported as an adverse event in 6.4% of patients treated with maribavir 400 mg twice daily during a Phase 3 clinical study. An earlier study found that patients treated with the highest dosage of 1,200 mg twice daily had a greater incidence of immunosuppressant drug level increase compared to patients treated with 400 mg twice daily, despite a similar safety profile overall.

MANAGEMENT: Caution is advised when maribavir is used concurrently with immunosuppressants that are CYP450 3A4 and/or P-gp substrates, most of which exhibit a narrow therapeutic range. Frequent monitoring of immunosuppressant drug level is recommended during treatment with maribavir, especially following initiation and up to 48 hours after its discontinuation, and the immunosuppressant dosage adjusted as necessary.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.