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

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.

Immunosuppressive drugs in whole blood: validation of a commercially available liquid chromatography/tandem mass spectrometry kit and comparison with immunochemical assays

“…A survey conducted by the International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) involving 76 laboratories in 14 countries identified liquid chromatography/tandem mass spectrometry (LC/MS/MS) as a major technique for the routine analysis of immunosuppressive agents. Specifically, LC/MS/MS was used for the determination of CSA, TACRO, SIRO, and EVE in 47%, 53%, 70%, and 75% of the laboratories surveyed, respectively . Extensive use of this method is due to its high specificity that is achieved with the separation of different molecules via liquid chromatography followed by the detection based on unique behavior of the molecular fragmentation.…”

Multi-center Performance Evaluations of Tacrolimus and Cyclosporine Electrochemiluminescence Immunoassays in the Asia-Pacific Region

“…Results generated with tacrolimus microparticle enzyme immunoassay (MEIA) II-IMx (Abbott Laboratories), which has been taken off the market, were shown to be strongly affected by the sample hematocrit. Lastly, in addition to a lack of standard reference methods, comparison of analytical procedures is hampered by the absence of certified reference materials [ 12 38 ]. Tacrolimus is the only ISD for which whole blood certified reference material is available (ERM-DA110a).…”

Could salivary cyclosporine dosage replace the whole blood cyclosporine measurements in renal transplant patients?

“…Several authors have suggested a clinical benefit of CsA monitoring using the CsA at C 2 , which correlates better with AUC than C 0 in different organ transplantation models. [218]…”

“…[2] Monitoring of whole blood levels consists of repeated sampling to determine the area under the time–concentration curve over a period of 4 h after administration (AUC 0–4h ). Although the 4-h AUC identifies the therapeutic window and enables avoidance of underdosing or overdosing, it is not practical in clinical practice.…”

“…The use of the single blood CsA concentration measured 2 h after administration (C 2 ) has been proposed as an alternative. [2] In addition to being easier to obtain as part of the patient's ongoing medical care,[2] single serum C 2 measures have been shown to correlate better with AUC 0–4h than trough levels (C 0 ) (CsA blood level before morning dose) and to better reflect the maximal immunosuppressive effect of CsA. [234567] Furthermore, the proportion of cluster of differentiation 4 (CD4+) lymphocytes producing interleukin-2 (IL-2) is the lowest at 2 h post-dose in renal transplant recipients.…”