Busulfan Pharmacokinetics and Precision Dosing: Are Patients with Fanconi Anemia Different?

Abstract It is well known that pharmacokinetics (PK) guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell transplantation (HCT). However, there are no published PK data in patients with Fanconi anemia (FA) who are known to have baseline DNA repair defect and related inherent sensitivity to chemotherapy. In our prospective, multi-institutional study of alternative donor HCT for FA using chemotherapy only conditioning, we replaced the single dose of total body irradiation (TBI) with BU at initial doses of 0.8-1.0 mg/kg and 0.6-0.8 mg/kg given IV every 12 hours for 4 doses. Patients received the first dose of IV busulfan on day -8 and blood levels for PK were obtained. PK samples were drawn following completion of infusion. BU PK levels were collected at 2 hrs, 2 hrs-15 mins, 4, 5, 6, and 8 hrs from the start of infusion. Remaining three doses of BU were given on days -7 and -6. Thirty seven patients with available BU PK data with a median age of 9.2 years (range: 4.3-44 yrs) are included in the final analyses. The overall BU PK profile in patients with FA is similar to non-FA patients after considering their body weight. In our cohort a strong correlation between BU clearance and weight supports current practice of per kg dosing. However, not surprisingly, we show that the disease i.e. host sensitivity related to FA is the main determinant of total dose of BU that can be safely administered to patients in this high risk population. Based on our results we propose an optimal BU Css level of ≤350ng/ml (equivalent to total cumulative exposure of 16.4 mg*h/L for 4 doses over 2 days) for patients with FA undergoing HCT. This is the first and largest report of prospective BU PK in patients with FA undergoing HCT, providing optimal BU target cut off to achieve stable donor engraftment while avoiding excessive toxicity.