Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once‐daily intravenous busulfan dosing nomogram

Abstract

Busulfan, a bifunctional alkylating agent, has been used as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to derive a novel once-daily intravenous (IV) busulfan dosing nomogram for pediatric patients undergoing HSCT using a population pharmacokinetic (PK) model. A population PK analysis was performed using 2183 busulfan concentrations in 137 pediatric patients (age: 0.6-22.2 years), who received IV busulfan once-daily for 4 days before undergoing HSCT. Based on the final population PK model, an optimal once-daily IV busulfan dosing nomogram was derived. The percentage of simulated patients achieving the daily target area under the concentration-time curve (AUC) by the new nomogram was compared with that by other busulfan dosing regimens including the FDA regimen, the EMA regimen, and the empirical once-daily regimen without therapeutic drug monitoring (TDM). A one-compartment open linear PK model incorporating patient's body surface area, age, dosing day, and aspartate aminotransferase as a significant covariate adequately described the concentration-time profiles of busulfan. An optimal dosing nomogram based on the PK model performed significantly better than the other dosing regimens, resulting in >60% of patients achieving the target AUC while the percentage of patients exceeding the toxic AUC level was kept <25% during the entire treatment period. A novel once-daily busulfan dosing nomogram for pediatric patients undergoing HSCT is useful for clinicians, particularly in a setting where TDM service is not readily available or to optimize the dose on day 1.

Favorable Outcome of Post-Transplantation Cyclophosphamide Haploidentical Peripheral Blood Stem Cell Transplantation with Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring in Pediatric Patients

“…Recently, similar nonrelapse mortality was observed in adult patients who underwent myeloablative haplo-HSCT with a busulfan-based regimen, when compared with those who received a nonmyeloablative conditioning regimen [20]. To improve the outcomes in pediatric patients using a busulfan-based myeloablative conditioning regimen, we optimized the busulfan exposure of each patient using daily TDM, which already showed a favorable clinical outcome [35], and acceptable busulfan pharmacokinetic results [34]. To the best of our knowledge, the present study includes the largest number of pediatric patients who underwent haplo-HSCT using PTCy along with a targeted busulfan-based myeloablative conditioning regimen.…”

“…In the present study, we used an intensive daily pharmacokinetic (PK) monitoring method for busulfan dosing and optimized the intensity of the conditioning regimen by calculating the total exposure of busulfan [33][34][35][36]. Here, we applied this targeted-busulfan method using the daily PK monitoring of haplo-HSCT using PTCy in pediatric patients, and the safety and outcomes were evaluated.…”

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

“…For GVHD prophylaxis, mycophenolate mofetil and tacrolimus were administered. Targeted IV busulfan was administered at a starting dose of 120 mg/m 2 , and subsequent doses were analyzed using daily therapeutic drug monitoring [9][10][11].…”

“…Median age at diagnosis 13 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) Gender WBC count of >100×10 9 /L at diagnosis; b) enocitabine, idarubicin, intrathecal cytarabine; c) cytarabine, idarubicin, mitoxantrone. Abbreviations: AML, acute myeloid leukemia; CR, complete remission; DOD, died of disease; FAB, French-American-British classification; HSCT, hematopoietic stem cell transplant; MRD, matched related donor; MUD, matched unrelated donor; N, number; TRM, treatment-related mortality.…”

New dosing nomogram and population pharmacokinetic model for young and very young children receiving busulfan for hematopoietic stem cell transplantation conditioning

“…As the “Observatory” was set up to study very young children (median weight = 12 kg), we developed a new Bu POP‐PK model and propose a novel dosing nomogram adapted to infants and young children. This new nomogram would be easy to use for clinicians in clinical practice and complementary to a novel once‐daily dosing regimen 21 …”