Highly Variable Pharmacokinetics of Once-Daily Intravenous Busulfan When Combined with Fludarabine in Pediatric Patients: Phase I Clinical Study for Determination of Optimal Once-Daily Busulfan Dose Using Pharmacokinetic Modeling

Busulfan has a narrow therapeutic range, and in children, pharmacokinetic variability has been found to be high even after the use of intravenous (i.v.) busulfan. Recently, a reduced toxicity myeloablative regimen showed promising results, but the data of busulfan pharmacokinetics in hematopoietic stem cell transplantation (HSCT) using a targeted busulfan/fludarabine regimen in children has not yet been reported. We performed therapeutic drug monitoring (TDM) after once-daily i.v. busulfan combined with fludarabine and analyzed the outcomes. Busulfan (i.v.) was administered once daily for 4 consecutive days. The daily target area under the curve (AUC) was 18,125-20,000 μg*h/L/day (4415-4872 μmol*min/L/day), which was reduced to 18,000-19,000 μg*h/L/day (4384-4628 μmol*min/L/day) after a high incidence of toxicity was observed. A total of 24 patients were enrolled. After infusion of busulfan on the first day, patients showed AUC that ranged from 12,079 to 31,660 μg*h/L (2942 to 7712 μmol*min/L) (median 16,824 μg*h/L, percent coefficient of variation (%CV) = 26.5%), with clearance of 1.74-6.94 mL/min/kg (median 4.03 mL/min/kg). We performed daily TDM in 20 patients, and during the daily TDM, the actual AUC ranged from 73% to 146% of the target AUC, showing high intraindividual variability. The %CV of busulfan clearance of each individual ranged from 7.7% to 38.7%. The total dose of busulfan administered for 4 days ranged from 287.3 mg/m² to 689.3 mg/m². Graft failure occurred in 3 patients with total AUC less than 74,000 μg*h/L (18,026 μmol*min/L), and 2 patients with relatively high total AUC experienced veno-occlusive disease. Busulfan pharmacokinetics showed high inter- and intraindividual variability in HSCT using a targeted busulfan/fludarabine regimen, which indicates the need for intensive monitoring and dose adjustment to improve the outcome of HSCT. Currently, we are performing a newly designed phase II study to decrease regimen-related toxicities and reduce graft failure by setting an optimal target AUC based on this study.