Drug Interactions between glucarpidase and levoleucovorin

ADJUST DOSING INTERVAL: Concomitant administration of glucarpidase may decrease the plasma concentrations of leucovorin, which is a substrate for glucarpidase. Conversely, leucovorin may interfere with the action of glucarpidase in the treatment of toxic plasma methotrexate concentrations in patients with impaired renal function by reducing the availability of glucarpidase, a recombinant bacterial enzyme that provides an alternate nonrenal pathway for methotrexate elimination by converting methotrexate to an inactive metabolite and glutamate. In a study of cancer patients receiving a high-dose methotrexate (>=1 g/m2) and leucovorin rescue regimen, intravenous administration of glucarpidase 50 units/kg two hours before leucovorin decreased the peak plasma concentration (Cmax) of the active 6S(-) enantiomer of leucovorin by 52% and its systemic exposure (AUC) by 33%. In addition, the Cmax and AUC of the active metabolite, 6S(-)5-methyltetrahydrofolate, decreased by more than 90% each. In another study performed in the absence of methotrexate, healthy adult subjects who were given glucarpidase 50 units/kg followed by 5 doses of leucovorin (150 mg/m2) at 2, 8, 14, 20 and 26 hours post-glucarpidase had a 47% reduction in the AUC of 6S(-)leucovorin after the 2-hour dose and a 22% reduction in the AUC after the 26-hour dose.

MANAGEMENT: Leucovorin should be continued following treatment with glucarpidase; however, it should not be administered within two hours before or two hours after a dose of glucarpidase. For the first 48 hours after glucarpidase administration, the same leucovorin dose as given prior to glucarpidase treatment is appropriate. Beyond 48 hours, the leucovorin dose should be based on the measured methotrexate concentration. Do not discontinue leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold. Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. Hydration and alkalinization of the urine should be continued as indicated.

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