Current challenges of body weight based intravenous busulfan dosing versus dose adjustment based on therapeutic drug monitoring
Abstract
Background. Busulfan in high doses is often used to substitute total body irradiation for bone marrow or hematopoietic stem cell transplantation (HSCT) conditioning therapy.
Its considerable pharmacokinetic variability and worrying adverse effect in case of extreme exposure warrants pharmacokinetic monitoring in both oral and intravenous forms. Previous works suggested that test pharmacokinetic study enables dose prediction for all of the rest doses given every 6 hourly for four days.
However, extensive case series observations and further studies indicate that the drug shows intra-individual variability challenging the first dose based prediction. Objectives.
The principal aim of this communication is to describe typical cases, where dose prediction based on post initial doses concentrations measurement and consequent area under the concentration versus time curve (AUC) calculation may not be reliable and that may endanger the principal goal of the intervention. Patients and Methods.
Data from three exemplary out layer cases have been processed from patients where prae-analysis provision of informed consent of a patient or the guardians in paediatric cases is standard. An adult male at age of 49 years, and two children (1 male and 1 female) both at age of 2 years, respectively have been treated with i.v. busulfan doses on body weight basis according to clinical protocol before HSCT.
Sampling was started with trough concentration (immediately before the 5th dose) followed by samples immediately after the end of 2-4 h lasting infusion (peak), 4 h, and 6 h from the starting time of the infusion utilizing limited sample strategy. Busulfan concentrations were determined by high performance liquid chromatography (HPLC).
AUC was calculated using the trapezoidal rule.