Therapeutic drug monitoring-guided dosing of busulfan differs from weight-based dosing in hematopoietic stem cell transplant patients

Abstract

Busulfan (Bu)-based preparative regimens in hematopoietic stem cell transplantation are commonly used. Previous studies have shown that Bu at a fixed dose of 3.2mg/kg/day (FBD) given intravenously decreases variability in drug pharmacokinetics and this decreases the dependency on therapeutic drug monitoring (TDM) of Bu. We compared the Bu dose given using TDM with the FBD of 3.2mg/kg/day. Seventy-three patients with acute leukemia, myelodysplasia, chronic myeloid leukemia, thalassemia major, and sickle cell disease were included. The mean age at transplant was 15years (range 2-55years) with 57% adults. Indication for transplantation was leukemia/myelodysplastic syndrome in 46% of the patients, while the remaining 54% were transplanted for inherited blood disorders. We found that the median FBD was lower than the median TDM dose by 39mg/day with a statistically significant difference (p<0.001) even after adjusting for the weight (median total FBD of 349mg, median TDM dose of 494mg, p<0.0001). Age and underlying condition (malignant vs. nonmalignant) were the main factors affecting Bu clearance (p<0.001 and p<0.07, respectively). TDM remains an important tool for the appropriate dosing of Bu in preparative regimens of hematopoietic stem cell transplantation, especially in populations with genetic admixture.

Raman spectroscopy as a potential tool for label free therapeutic drug monitoring in human serum: the case of busulfan and methotrexate

“…This Raman spectral response was validated to be linear over the entire range of 0.0003mg/mL to 0.0125mg/mL, which has not been fully validated in previous studies. In comparison to the earlier studies based on LC-MS, the present method shows similar performances in precision and recovery (13,16,24,56). However, In contrast, the proposed method with inverted Raman spectroscopy is cost-effective and easy to use, that can be translated as a point-of-care diagnostic tool for high-dosage MTX in bodily fluids.…”

“…Busulfan (Bu) is a bi-functional alkylating agent (see chemical structure in inset of Figure 2A) used in the chemotherapy-based conditioning regimen for hematopoietic stem cell transplantation (HSCT) (9)(10)(11)(12)(13)(14)(15)(16)(17). Bu has a very narrow therapeutic index, and higher systemic exposure to Bu is related to hepatic sinusoidal obstruction syndrome, neurotoxicity or insterstitial pneumonia, while low levels have been shown to be associated with increased incidence of graft rejection (18)(19)(20)(21).…”

Applications and challenges in therapeutic drug monitoring of cancer treatment: A review

“…High Bu exposure, measured as an AUC > 1350 µM.min, is associated with toxicity, such as the development of acute graft-versus-host-disease (GvHD) and veno-occlusive disease (VOD) of the liver, whereas underexposure to Bu (AUC < 900 µM.min) increases the risk of graft rejection or relapse. 22…”

Optimal cancer drug dosing in adolescents: new issues and the old unaddressed ones

“…TDM is essential to ensure adequate methotrexate levels in acute lymphoblastic leukaemia (ALL) and solid tumour protocols and has led to improved outcomes. Busulfan, with its narrow therapeutic window for both effect and toxicity, requires TDM to ensure optimised outcomes in AYA patients, as age has been demonstrated to impact significantly on clearance, and significantly higher clearance is seen in younger patients . As TDM is not widely used when dosing other cytotoxic agents, knowledge of the issues mentioned in Table and local experience has traditionally been relied on to titrate the dose of many drugs for AYA in most centres.…”