Busulfan Interlaboratory Proficiency Testing Program Revealed Worldwide Errors in Drug Quantitation and Dose Recommendations

Therapeutic Drug Monitoring, vol. 45, pp. 760–765

Abstract

BACKGROUND: The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively. METHODS: A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with ±15% for busulfan concentrations and ±10% for busulfan plasma exposure. The dose recommendations were deemed accurate. RESULTS: Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values. CONCLUSIONS: The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.

Authors 5

1. Dina M. Kweekel corresponding Aachen Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands;

   Drug Analysis and Toxicology Division (KKGT) of the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML), Utrecht, The Netherlands;

2. Jeannine S. McCune

   City Of Hope National Medical Center · City of Hope · Beckman Research Institute

   Affiliation as printed

   Department of Hematologic Malignancies Translational Sciences and Department of Hematologic Malignancies & HCT, Beckman Research Institute of City of Hope, Duarte, California;

3. Arjen M. Punt

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands;

   Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands;

4. Matthijs van Luin

   University Medical Center Utrecht

   Affiliation as printed

   Department of Clinical Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands; and

   Drug Analysis and Toxicology Division (KKGT) of the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML), Utrecht, The Netherlands;

5. Eric J. F. Franssen corresponding

   OLVG

   Affiliation as printed

   Department of Clinical Pharmacy OLVG, Amsterdam, The Netherlands

   Drug Analysis and Toxicology Division (KKGT) of the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML), Utrecht, The Netherlands;