Drug Interactions between idarubicin and Omeclamox-Pak

MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of daunorubicin and idarubicin, both of which are substrates of the efflux transporter also known as ABCB1 or MDR1. The interaction has been studied with cyclosporine, a potent P-gp inhibitor, in attempt to overcome multidrug resistance in MDR1-overexpressing tumors. In a randomized study to test whether cyclosporine can enhance the antileukemia effect of anthracyclines, cyclosporine was found to significantly reduce the frequency of resistance to induction chemotherapy consisting of sequential cytarabine and daunorubicin (31% vs. 47%). The addition of cyclosporine also increased relapse-free and overall survival, particularly in patients with moderate or high P-gp expression. Pharmacokinetically, steady-state mean serum concentrations of daunorubicin and its active metabolite, daunorubicinol, were significantly higher (approximately 2-fold and 4-fold, respectively) in patients receiving cyclosporine. Although there was no significant difference in the frequency or severity of stomatitis or renal toxicity (as measured by creatinine elevation), grade 4 hyperbilirubinemia and grade 3 nausea occurred more frequently in patients receiving cyclosporine than in controls (31% vs. 4% and 11% vs. 3%, respectively). In a pharmacokinetic study of 27 patients with acute myelogenous leukemia receiving induction chemotherapy with idarubicin and cytarabine, the systemic exposure (AUC) to idarubicin and idarubicinol was increased by 77% and 182%, respectively, in patients administered cyclosporine 10 mg/kg daily compared to controls due to a 40% reduction in total body clearance. The interaction was also reported in another study in which increases in the AUC of idarubicin and idarubicinol were associated with increased levels of toxicity.

MANAGEMENT: Caution is advised if daunorubicin or idarubicin is prescribed in combination with a P-gp inhibitor. Patients should be closely monitored for increased adverse effects including cardiotoxicity and myelosuppression.

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Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

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