A test dose of I.V. busulfan (BU) is predictive of the area under the curve (AUC) of a single daily dose of I.V. bu in pediatric patients undergoing a reduced intensity (RI) hematopoietic stem cell transplant (HSCT)

Abstract

High-dose BU-containing chemotherapy has been used in autologous and allogeneic HSCT. Variations in the PK for oral BU in pediatric patients have resulted in either decreased effect or increased toxicity. The IV formulation eliminates the variability of absorption . A simple method to assess PK AUC of single dose/24hrs of IV BU in pediatric patients is described. Patients who signed informed consent were enrolled. The regimen consisted of test dose of IV BU (0.8mg/kg) as a single dose day -10, Fludarabine 30mg/m2/day on days −10 to −6, followed by BU 3.2 mg per Kg/day on days −5 and −4 and rabbit ATG 2mg/kg on days −4 to −1. Phenytoin prophylaxis was given for 4 days. Cells were infused on day 0. There were 5 patients with a median age 8.0 (0.5–16 years);. The median weight was 22.6 (range 4.3–45.4) Kg. Patients diagnoses include: Omenn’s syndrome, Neuroblastoma, ALL, CML, and X linked lymphoproliferative disease. Samples were obtained at 2, 4, 8 and 12 hrs and submitted to the Fred Hutchinson Cancer Center for determination of the AUC. An AUC of 800–1200 was targeted for the test dose. The median measured AUC was 1034 (816–1315) uMol∗min; the clearance was 3.1 (2.4–3.9) (ml/min) kg. The target AUC equals the AUC of the test dose multiplied by 4. The dose of 3.2mg/Kg/q24 hrs was administered and the target AUC was 3800–4200. The measured AUC median was 3590 (2307–4097) uMol∗min and the clearance 3.4 (3–4.2)(ml/min)/kg, Dose adjustment of 10% lower dose on days −5, −4 was made on one patient who had a high AUC, the modification resulted in a lower AUC. No instances of hepatic veno-occlusive disease or seizures developed. Neutrophil and platelet engraftment was prompt in 3/3 evaluable patients. Three of the patients have achieved full chimerism. In conclusion, PK of a test dose of 0.8 mg/Kg of IV BU multiplied by 4 appears to be predictive of the PK for a single daily dose of IV BU in pediatric patients undergoing a RI HSCT.