Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin

Busulfan (Bu) conditioning used in hematopoietic stem cell transplantation may induce seizures, and prophylactic antiepileptic treatment is recommended. Following updated guidelines, in August 2019, the adult hematopoietic stem cell transplantation department of the Rambam Health Care Campus (Haifa, Israel) switched the antiepileptic prophylaxis protocol from phenytoin to oral levetiracetam during oral Bu conditioning. The aim of this study was to compare the pharmacokinetic parameters of Bu after oral dosing between patients receiving phenytoin and those receiving levetiracetam prophylaxis.This study was a retrospective cohort study in adults undergoing myoablative conditioning with oral Bu between August 2018 and August 2020. Bu pharmacokinetic parameters (AUC0-6, C0, Cmax, and Tmax) were compared in patients treated with phenytoin comedication (during the year before the change in policy) and levetiracetam comedication (during the year after the change). Potential confounders were accounted for including age, azole comedication, and body weight.There were no significant differences in demographic and clinical parameters or weight-corrected Bu dose between the phenytoin group (n = 28) and the levetiracetam group (n = 25). There was no difference in the rate of voriconazole comedication, but fluconazole was more common in the phenytoin group (P = 0.026). The median AUC0-6 was significantly lower in the levetiracetam group (949 μM*min; IQR = 806 to 1101 μM*min) than in the phenytoin group (1208 μM*min; IQR = 1087 to 1389 μM*min; P < 0.001). This is a clinically significant difference of 258 μM*min (21%). Azole use was not associated with Bu exposure.The findings suggest that, after treatment with oral Bu, oral levetiracetam comedication is associated with reduced systemic exposure compared with phenytoin comedication, possibly because of decreased bioavailability.