Clinical consequences of analytical variance and calculation strategy in oral busulfan pharmacokinetics

Abstract

BackgroundBusulfan pharmacokinetic (PK) monitoring of the area under the concentration–time curve (AUC) is necessary to minimize adverse events associated with both under- and over-dosing of busulfan during hematopoietic stem cell transplantation (HSCT). Three strategies are frequently used to calculate the AUC including in-house polynomial methods, the trapezoidal method (also called noncompartmental analysis), and the single compartment model with first-order elimination method. We compared these 3 methods, their clinical performance, and the relationship of AUC variance to analytical variance when each of these methods is used. MethodsClinical busulfan PK data was reviewed from 159 patients receiving the first dose of oral busulfan while undergoing HSCT. These data were used as templates to simulate AUC results and actions with varying amounts of analytical precision. ResultsBased on a predefined goal therapeutic target, the method for calculating AUC significantly changed the number of recommended busulfan dose adjustments (p<0.000001). Overall, the number of dose adjustments would be expected to drop by approximately 10% due to calibration optimization of the busulfan concentration measurement method. ConclusionAnalytical variance and the AUC calculation method play a considerable role in the clinical management of busulfan dosing during HSCT. With better understanding and optimization of the analytical method, the reliability of clinically actionable information from busulfan PK can increase.