Pharmacokinetics of high-dose busulfan in children

Abstract

The pharmacokinetics of high-dose busulfan given orally at 1 mg/kg every 6 h over 4 days (total dose, 16 mg/kg) in combined chemotherapy followed by autologous bone marrow transplantation was studied in 12 children with a mean age of 7 years (range, 4-14 years). Busulfan levels in biological fluids were measured by a gas chromatographic assay with mass fragmentographic detection, using a deuterated analogue as the internal standard. In a high-dose regimen, busulfan followed one-compartment model kinetics with zero-order absorption. A mean maximal concentration of 803 +/- 228 ng/ml was achieved at 92-255 min after dosing. The mean elimination half-life was 2.33 h, and the mean total clearance was 119 +/- 54 ml/min per m2, with an apparent distribution volume of 27.10 +/- 11.50 l/m2. A mean trough level of 370 ng/ml was found throughout the 4 days of the chemotherapy course. There were no significant variations in pharmacokinetic parameters measured after the first and last doses. Busulfan was monitored in the CSF of nine children at 3.25-7 h after the last dose and was detected in all patients, with a mean CSF-to-plasma concentration ratio of 0.95 (range, 0.5-1.4).

Exposure equivalence between IV (0.8 mg/kg) and oral (1 mg/kg) busulfan in adult patients

“…For the high-dose Bu conditioning regimen, the situation is complex as the usual schedule consists of 16 doses administered every 6 h over only 4 days. To avoid any chronopharmacokinetic influence [27,28], PK assessments are generally conducted in the morning of days 1, 2, 3 and 4, i.e. at doses 1, 5, 9 and 13.…”

Busulfan pharmacokinetics do not predict relapse in acute myeloid leukemia

“…4 It has been determined that BU pharmacokinetic parameters do differ between children and adults. 5 However, attempts to correlate this data with engraftment, toxicity, or relapse have not led to definitive or consistent findings.Children have been found to have consistently lower peak BU concentrations, higher rates of drug clearance, higher volumes of distribution, and lower area-under-thecurve (AUC) concentrations than adults. 5-7 These BU pharmacokinetic parameters are influenced by the underlying disease, age, circadian rhythms, disease stage and drug interactions.…”

“…4 It has been determined that BU pharmacokinetic parameters do differ between children and adults. 5 However, attempts to correlate this data with engraftment, toxicity, or relapse have not led to definitive or consistent findings.…”

Correction of neutropenia and hypogammaglobulinemia in X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation

“…The choice of this regimen rather than a busulfan containing regimen was based on the known difficulties encountered in maintaining adequate busulfan levels in pediatric patients to produce ablation without unacceptable toxicity. 20,21 Transplantation was performed with 1.7 × 10 8 mononuclear cells/5.6 × 10 6 CD34 + cells per kg body weight. Prophylaxis for graft-versus-host disease was given including cyclosporin A (4 mg/kg/day i.v.…”