Drug Interactions between atovaquone / proguanil and glucarpidase

MONITOR: Concomitant administration of glucarpidase may decrease the plasma concentrations and effects of reduced folates and folate antimetabolites, which are potential exogenous substrates of glucarpidase. The interaction has been studied and reported with leucovorin (folinic acid). 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. Conversely, potential substrates of glucarpidase may interfere with its action 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.

MANAGEMENT: On theoretical grounds, caution is advised if glucarpidase is administered in combination with potential substrates such as folate antimetabolites other than methotrexate. With leucovorin, experts recommend administering it two to four hours before or after a dose of glucarpidase. The same precaution may be appropriate with other potential substrates of glucarpidase, although clinical data are currently lacking.