ITRACONAZOLE CAN INCREASE SYSTEMIC EXPOSURE TO BUSULFAN IN PATIENTS GIVEN BONE-MARROW TRANSPLANTATION

Busulfan (BU) is an alkylating drug frequently used to prepare patient s for bone marrow transplantation (BMT). Several studies have document ed that there is important interpatient variability in BU disposition and systemic exposure, and that other drugs with a common metabolic pa thway are capable of influencing BU clearance. We compared the BU phar macokinetics and pharmacodynamics of 13 patients given BMT and receivi ng BU and itraconazole, with those of 26 matched controls who did not receive any anti-fungal agent, and with those of 13 matched patients t reated with fluconazole as prophylaxis against fungal infections. The effect of itraconazole was best reflected in BU clearance since the BU dose was modified in some patients. BU clearance was decreased by an average of 20% in patients receiving itraconazole as compared to contr ol patients and patients receiving fluconazole (p < 0.01). Mean BU cle arance wa 7.653 +/- 1.871 l/hr.m(2) in the itraconazole patients, 10.1 03 +/- 2.007 l/hr.m(2) in the fluconazole group and 9.373 +/- 1.702 l/ hr.m(2) in the control group. In this study itraconazole, but not fluc onazole, markedly affected the pharmacokinetics of BU as an increase o f BU plasma concentrations was observed. The nature of this interactio n has not yet been fully characterized. Itraconazole and its analogues are inhibitors of both cytochrome P450 and lipoxygenase and since itr aconazole can modulate BU pharmacokinetics, oxidative catabolism is pr obably a determinant of BU metabolism. This hypothesis should be teste d in human metabolic studies.