A Simple Dosing Scheme for Intravenous Busulfan Based on Retrospective Population Pharmacokinetic Analysis in Korean Patients

Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (Vd) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and Vd were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC0-inf (defined as median AUC0-inf with a once-daily dosage) of 26.18 mg/lxhr, was proposed: 24.79xABW0.5 mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW.

The Effectiveness of Once-daily Intravenous Busulfan as a Conditioning Regime for Hematopoietic Stem Cell Transplantation in Children with Acute Myelogenous Leukemia

BACKGROUND: There have recently been some reports suggesting that once-daily intravenous busulfan (IV Bu) as a conditioning regime for hematopoietic stem cell transplantation (HSCT) possibly reduces the toxicities without influencing the clinical outcome as compared with the traditional 4 times daily dosage schedule. We report here on the clinical outcome of once-daily IV Bu as a conditioning regime for HSCT in children with AML at a single treatment center. METHODS: We retrospectively analyzed nine AML children who received HSCT with using the once-daily IV Bu (110~130 mg/m2 on 4 consecutive days) conditioning regimen at the Department of Pediatrics, Pusan National University Hospital from 2003 to 2007. RESULTS: The median age at HSCT was 8.25 years. As for the conditioning regimens, the HLA-matched sibling peripheral HSCT (N=4) was Flu/Bu, the CBT and unrelated BMT (N=4) was Flu/Bu/ATG and the autologous HSCT (N=1) was Bu/Cy. There was only one case of primary graft failure in an unrelated donor CBT recipient. The median time to neutrophil engraftment was 14 days and the median time to platelet engraftment was 19 days. The transplant-related toxicities were acceptable; there were no case with CNS toxicity and VOD was observed in two cases (1 mild case of VOD and 1 moderate case of VOD). Acute GVHD was noted in two cases (1 case of grade I and 1 case of IV). With a median follow up of 33 months, there were two cases of relapse and two cases of death. CONCLUSION: Once-daily IV Bu as a conditioning regimen for HSCT in children with AML was well tolerated and convenient with relatively moderate toxicities, but additional studies are needed to determine the therapeutic efficacy and pharmacokinetics of once-daily IV Bu in children who are undergoing HSCT.

Safety and Pharmacokinetics of Intravenous Busulfan as Conditioning prior to Allogeneic Stem Cell Transplantation / 대한혈액학회지

BACKGROUND: The unpredictable intestinal absorption and bioavailability of oral busulfan (BU) has limited the drug's use in high-dose pretransplant conditioning therapy. To overcome these problems, several trials for the evaluation of pharmacokinetics and clinical usefulness of an intravenous BU (IVBU) formulation have been reported. Here we present clinical and pharmacokinetic data on patients receiving IVBU as a component of conditioning regimens for allogeneic stem cell transplantation (SCT) in our center. METHODS: A total of 6 adult patients were entered onto this study. All patients were treated with IVBU (0.8mg/kg every 6 hours x 8~16)-containing conditioning regimen followed by HLA-identical allogeneic SCT. We also investigated the pharmacokinetics of IVBU using high-performance liquid chromatography in two cases. RESULTS: All patients achieved successful engraftment. No patient experienced hepatic veno-occlusive disease or neurologic toxicity. Five of 6 patients still alive in complete remission have been followed for 8~12 months after SCT. The measured maximum concentration for the first dose was 1,175ng/mL and 951ng/mL, and the half-life was 2.25h and 3.09h, respectively. The area under the plasma concentration-time curve was 4,596ng h/ mL and 3,067ng h/mL, respectively. There was no significant difference between the first and last dose pharmacokinetic parameters. CONCLUSION: We suggest that IVBU should be considered as appropriate replacement for oral BU in pretransplant conditioning therapy prior to SCT in Korea. Further studies with sizable patients are needed to define the role of IVBU in SCT setting.