Ann Lab Med.  2021 May;41(3):268-276. 10.3343/alm.2021.41.3.268.

Immunosuppressive Drug Measurement by Liquid Chromatography Coupled to Tandem Mass Spectrometry: Interlaboratory Comparison in the Korean Clinical Laboratories

Affiliations
  • 1Department of Laboratory Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
  • 2Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 3Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
  • 4Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
  • 5Department of Laboratory Medicine, Seoul National University Hospital and College of Medicine, Seoul, Korea
  • 6Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
  • 7Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
  • 8Seoul Clinical Laboratories, Yongin, Korea
  • 9Green Cross Laboratories, Yongin, Korea
  • 10Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
  • 11Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea

Abstract

Background
Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is increasingly used for immunosuppressive drug tests. However, most LC-MS/MS tests are laboratory-developed and their agreement is unknown in different Korean laboratories. This interlaboratory comparison study evaluated test reproducibility and identified potential error sources.
Methods
Test samples containing three concentrations of tacrolimus, sirolimus, everolimus, cyclosporine, and mycophenolic acid were prepared by pooling surplus samples from patients undergoing routine therapeutic drug monitoring and tested in duplicate in the participating 10 clinical laboratories. Reconstitution and storage experiments were conducted for the commonly used commercial calibrator set. The robust estimators of reproducibility parameters were calculated. Spearman’s rank correlation coefficient (rho, ρ) was used to evaluate the correlation between drugs. Multiple linear regression was used to determine whether the experimental conditions alter the calibration curves.
Results
The reproducibility coefficient of variation exceeded 10% only for sirolimus concentrations 1 and 2 (10.8% and 12.5%, respectively) and everolimus concentrations 1 and 2 (12.3% and 11.4%, respectively). The percent difference values showed weak correlations between sirolimus and everolimus (ρ = 0.334, P = 0.175). The everolimus calibration curve slope was significantly altered after reconstitution following prolonged 5°C storage (P = 0.015 for 14 days; P = 0.025 for 28 days); the expected differences at 6 ng/mL were 0.598% for 14 days and 0.384% for 28 days.
Conclusions
LC-MS/MS test reproducibility for immunosuppressive drugs seems to be good in the Korean clinical laboratories. Continuous efforts are required to achieve test standardization and harmonization, especially for sirolimus and everolimus.

Keyword

Immunosuppressive drug; Therapeutic drug monitoring; Liquid chromatography coupled to tandem mass spectrometry; Interlaboratory comparison; Sirolimus; Everolimus; Reproducibility
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