Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies

We investigated whether adjusting the oral busulfan (BU) dosage on the basi s of early pharmacokinetic data to achieve a targeted drug exposure could r educe transplant-related complications in children with advanced hematologi c malignancies. Twenty-five children received a preparative regimen consist ing of thiotepa (250 mg/m(2) i.v. daily for 3 days), BU (40 mg/m(2) per dos e p.o. every 6 h for 12 doses), and cyclophosphamide (60 mg/kg i.v. daily f or 2 days) and then underwent allogeneic stem cell transplantation. Busulfa n clearance and area under concentration time-curve (AUC) were determined a fter the first dose using a one-compartment pharmacokinetic (PK) model with first-order absorption. The initial PK analysis was successfully completed after the first BU dose in 21 patients (84%). A final AUC of 1000-1500 mu M x min/dose was targeted and subsequent doses were modified as necessary t o achieve this value. Fourteen of the 25 patients (56%) required dose adjus tment. Followup PK analysis was completed in 21 patients and 16 of these ac hieved the targeted BU exposure for the course of therapy. Interpatient var iability in BU clearance was high (up to five-fold), The most frequent regi men-related toxicities were cutaneous and gastrointestinal (stomatitis and diarrhea), Only one patient developed hepatic veno-occlusive disease, Our s tudy demonstrates the feasibility of adjusting the oral BU dose in individu al pediatric patients. Although toxicity associated with BU seemed to be re duced, this conclusion is tempered by the fact that the overall regimen-rel ated toxicity (RRT) remains substantial and reflected the effects of all ag ents used in the preparative regimen.