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

Abstract

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/m(2) to 689.3 mg/m(2). 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.

Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

“…As a result, there is a large interpatient variability in busulfan clearance. Lee et al [24] observed clearance rates from 1.74 to 6.94 mL/min/kg after administration of a oncedaily dose of 120 mg/m 2 in 23 children aged .9 to 18.1 years (median, 9.3 years). This was echoed by Nath et al [25], who observed a coefficient of variation of 35% in the clearance of busulfan in 40 children.…”

Granulocyte colony-stimulating factor (G-CSF) promotes spermatogenic regeneration from surviving spermatogonia after high-dose alkylating chemotherapy

“…While it is not possible to directly compare the results from different experimental groups because each received different treatment regimens, future studies might explore methods to improve reliability of busulfan sterilization, alternative agents (e.g., cyclophosphamide), or use of irradiation. Highly variable busulfan pharmacokinetics in human patients, even intra-individually, is well known [38–41]. Therefore, although we took great care to ensure accurate busulfan dosing and employed an inbred mouse strain to reduce the influence of genetic modifiers on the experimental outcomes, differences in busulfan pharmacokinetics between individual animals could have led to the variability in busulfan efficacy we observed.…”

Targeted busulfan and fludarabine-based conditioning for bone marrow transplantation in chronic granulomatous disease

“…Consequently, the variability of daily AUC was high, but the total AUC of the 4 days approached the target AUC. Because hepatic toxicity and VOD are associated with high total AUC level, a total target AUC <77,000 µg·hr/L was recommended to reduce the toxicity and improve the outcome of HSCT1). There was no definite HSCT-related toxicity related observed in our patient, and this may have been be assisted by busulfan dose adjustment based on TDM.…”

“…On the first day, the patient received 120 mg/m 2 of busulfan, and targeted dose of busulfan was administered on subsequent three days. The target area under curve (AUC) of busulfan was 18,500–19,000 µg·hr/L, and the target cumulative AUC of busulfan for the 4 days was 75,000 µg·hr/L1). The total cumulative AUC of busulfan that was administered over 4 days was 73,148.1 µg·hr/L, with a daily AUC of busulfan of 22,043.7 µg·hr/L, 21,250.2 µg·hr/L, 19,691.5 µg·hr/L, and 10,162.7 µg·hr/L.…”