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Impact of Laboratory Practices on Interlaboratory Variability in Therapeutic Drug Monitoring of Immunosuppressive Drugs

Christians, Uwe MD, PhD*; Vinks, Alexander A. PharmD, PhD; Langman, Loralie J. PhD; Clarke, William PhD§; Wallemacq, Pierre PhD; van Gelder, Teun MD, PhD**; Renjen, Varun MD††; Marquet, Pierre MD, PhD; Meyer, Eric J. BS‡‡

doi: 10.1097/FTD.0000000000000205
Original Article

Abstract: The immunosuppressants cyclosporine, tacrolimus, sirolimus, everolimus, and probably also mycophenolic acid require therapeutic drug monitoring (TDM)–guided dosing to ensure that blood concentrations are kept within the target range in transplant patients. Reliable, accurate, and precise test methods are therefore essential to effectively monitor levels and to make proper dose adjustments. Data from proficiency testing programs have shown substantial interlaboratory variability. Only few attempts have been made to study the underlying causes. The aim of this study was to systematically document current practices used for immunosuppressant drug TDM in clinical laboratories and identify methodological and practice differences, which may cause the variability observed among laboratories. Data collection was primarily conducted by a structured Web-based survey. Invitations to participate in the survey were distributed to clinical laboratories providing immunosuppressant drug TDM. Surveys were completed by 76 laboratories in 14 countries. The results of our survey suggest that there are 3 main reasons for interlaboratory variability: (1) lack of standardization of laboratory procedures and workflows starting with sample collection and handling, (2) lack of use of appropriate reference materials (eg, isotope-labeled internal standards for liquid chromatography–tandem mass spectroscopy), and (3) poor compliance with internationally accepted good laboratory practice guidelines (eg, related to quality control, quality assurance, validation, training of personnel). The results of the survey also suggest that interlaboratory variability is a multifactorial problem. Technical-level consensus on laboratory operational procedures, quality systems, and personnel training will be of great importance to improve quality and interlaboratory comparability.

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*iC42 Clinical Research and Development, University of Colorado, Aurora;

Department of Pediatrics, Division of Clinical Pharmacology, Cincinnati Children's Hospital and Medical Center, College of Medicine, University of Cincinnati, Ohio;

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;

§Department of Clinical Toxicology, Johns Hopkins School of Medicine, Baltimore, Maryland;

Department of Pharmacology, Toxicology and Pharmacovigilance, University Hospital of Limoges, France;

Cliniques Universitaires St. Luc, UCL, Brussels, Belgium;

**Departments of Hospital Pharmacy and Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands;

††Navigant Consulting Inc, New York, New York; and

‡‡Novartis Pharmaceutical Corp, East Hanover, New Jersey.

Correspondence: Uwe Christians, MD, PhD, iC42 Clinical Research and Development, University of Colorado, Anschutz Medical Campus, 1999 N. Fitzsimons Parkway, Suite 100, Aurora, CO 80045-7503 (e-mail:

Supported by Novartis Pharmaceuticals Corp, East Hanover, NJ, and supported and endorsed by the International Association for Therapeutic Drug Monitoring and Clinical Toxicology.

U. Christians has received research funding from Novartis, Roche Diagnostics, Thermo Fisher, Waters, Fujirebio, and Siemens Healthcare. A. A. Vinks has received research funds from Roche Laboratories. W. Clarke has received research funding from Thermo Fisher Scientific and has consulted for Thermo Fisher Scientific and Roche Diagnostics. P. Marquet has received research funding from Novartis. E. J. Meyer is an employee of Novartis Pharmaceuticals Corp, East Hanover, NJ. The remaining authors declare no conflict of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received December 09, 2014

Accepted February 26, 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.