Seizure prophylaxis and its impact on busulfan pharmacokinetics and dosing in a novel timed sequential protocol: MD Anderson experience.

Abstract

High dose busulfan (Bu) is widely used in conditioning regimens for patients undergoing hematopoietic stem cell transplantation. Like all alkylating agents, it has significant inter-patient pharmacokinetic (PK) variability. The influence of Bu plasma exposure on treatment outcomes and toxicities have led to the continued use of therapeutic drug monitoring of Bu. We investigated Bu PK in a unique myeloablative fractionated Bu regimen, designed to lower non-relapse mortality in older patients and those with comorbidities. Intravenous (IV) Bu was administered once daily for 6 days, with a 7-day break after the first 2 Bu doses. Since seizures are a major risk of high-dose Bu, phenytoin was given as seizure prophylaxis. In an interim analysis, we noted a substantially increased (14.7%) Bu clearance on day -6 compared with day -13. When phenytoin was replaced by levetiracetam, Bu clearance increased by only 4.9% between days -13 and -6, significantly lower than that observed with phenytoin (p=0.00001). These results indicate the presence of a drug-drug interaction (DDI) between Bu and phenytoin. There was no difference in efficacy of seizure prophylaxis between phenytoin and levetiracetam, and there were no experienced adverse events related to levetiracetam. Our results indicate that levetiracetam is a safe and efficacious alternative to phenytoin for seizure prophylaxis in Bu-based conditioning regimens in stem cell transplantation, notably without the significant drug-drug interaction observed with phenytoin.