Quality Control of Busulfan Plasma Quantitation, Modeling, and Dosing: An Interlaboratory Proficiency Testing Program

Abstract

Background: Personalizing busulfan doses to target a narrow plasma exposure has improved the efficacy and lowered the toxicity of busulfan-based conditioning regimens used in hematopoietic cell transplant. Regional regulations guide interlaboratory proficiency testing for busulfan concentration quantification and monitoring. To date, there have been no comparisons of the busulfan pharmacokinetic modeling and dose recommendation protocols used in these laboratories. Here, in collaboration with the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring and Clinical Toxicology, a novel interlaboratory proficiency program for the quantitation in plasma, pharmacokinetic modeling, and dosing of busulfan was designed. The methods and results of the first 2 rounds of this proficiency testing are described herein.Methods: A novel method was developed to stabilize busulfan in N,N-dimethylacetamide, which allowed shipping of the proficiency samples without dry ice. In each round, participating laboratories reported their results for 2 proficiency samples (one low and one high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. All participants were blinded to the answers; descriptive statistics were used to evaluate their overall performance. The guidelines suggested that answers within 615% for busulfan concentrations and 610% for busulfan plasma exposure and dose recommendation were to be considered accurate.Results: Of the 4 proficiency samples evaluated, between 67% and 85% of the busulfan quantitation results were accurate (ie, within 85%-115% of the reference value). The majority (88% round #1; 71% round #2) of the dose recommendation answers were correct.Conclusions: A proficiency testing program by which laboratories are alerted to inaccuracies in their quantitation, pharmacokinetic modeling, and dose recommendations for busulfan in hematopoietic cell transplant recipients was developed. These rounds of proficiency testing suggests that additional educational efforts and proficiency rounds are needed to ensure appropriate busulfan dosing.

Automation in Busulfan Therapeutic Drug Monitoring: Evaluation of an Immunoassay on two Routine Chemistry Analyzers

“…DMA was also used to dilute the stock solution to obtain different working solutions that were spiked in blank calf serum (90 µL working solution in 1 mL matrix; 8.3% v/v). 9 This hypothesis was verified by spiking all four LC-HRMS QC levels with increasing amounts of DMA (from 0% to 11% v/v). Despite the 1/10 dilution of the samples, DMA concentration-dependent increases in busulfan immunoassay results were obtained (see Figure 1 , Supplementary Digital Content , http://links.lww.com/TDM/A530).…”

“…The busulfan concentrations ranged from 226 to 1401 ng/mL, covering the linearity range of the immunoassay. According to McCune et al, 9 busulfan concentrations should not deviate by more than 615%. This criterion was used in a proficiency testing program.…”

“…To finalize our validation, samples from a Dutch interlaboratory proficiency testing program 9 were analyzed using the immunoassay and LC-HRMS method. The results are presented in Supplementary Digital Content (see Table 1 , http://links.lww.com/TDM/A530).…”

“…Currently, no laboratories (n = 27) that participated in the proficiency testing program used an immunoassay to quantitate busulfan. 9 DMA is a frequently used excipient in intravenous busulfan formulations. However, the highest observed DMA plasma concentration after high-dose intravenous busulfan was 3.09 mmol/L 12 (corresponding to 0.03% v/v), which is well below the lowest spiked concentration in our experiment.…”

“…This criterion was used in a proficiency testing program. 9 Excel (Microsoft Corporation, Redmond, WA) and Medcalc software (Mariakerke, Belgium) programs were used for the data analysis.…”