Long‐term evaluation of analytical methods used in sirolimus therapeutic drug monitoring

Abstract

Results of therapeutic monitoring of sirolimus blood concentrations are assay and laboratory dependent. This study compared performance over time of the IMx microparticle enzyme immunoassay (MEIA), Architect chemiluminescent microparticle immunoassay (CMIA), and liquid chromatography with mass spectrometric detection (LC/MS/MS) as part of a proficiency testing scheme. Pooled samples from sirolimus-treated patients and whole-blood samples spiked with known quantities of sirolimus were assayed monthly between 2004 and 2012. When results of pooled patient samples were compared with LC/MS/MS, the MEIA assay showed an overall mean percent bias of -2.3% ± 11.2% that, although initially positive, became increasingly negative from 2007 through 2009. The CMIA, which replaced the MEIA assay, had a mean percent bias of 21.9% ± 12.3%, remaining stable from 2007 through 2012. Similarly, for spiked samples, the MEIA showed an increasingly negative bias over time vs. LC/MS/MS, whereas CMIA maintained a stable positive bias. Based on comparison of immunoassay measurements on individual patient samples, CMIA values were more than 25% higher than MEIA values. These results highlight the importance of continued proficiency testing and regular monitoring of sirolimus assay performance. Clinicians must be aware of the methodology used and adjust target levels accordingly to avoid potential effects on efficacy and toxicity.

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

“…Possible reasons for this deviation have been reported [ 12 ]. Firstly, calibration bias and between-method bias may change with time, as observed for the sirolimus microparticle enzyme immunoassay [ 35 ]. Secondly, cross-reactivity with other drugs and metabolites may occur; false-positives, most probably because of heterophilic antibodies, have been reported for immunoassays based on the ACMIA format [ 12 36 37 ].…”

Simultaneous quantification of cyclosporin, tacrolimus, sirolimus and everolimus in whole blood by UHPLC–MS/MS for therapeutic drug monitoring

“…However, LC-MS/MS methods are generally considered the gold standard due to their high sensitivity, selectivity and specificity (Zhang & Zhang, 2018). Microparticle enzyme immunoassay (MEIA) and architect chemiluminescent microparticle immunoassay (CMIA) showed a significant bias from each other and when compared with LC-MS/MS assay for TDM of SIR blood concentrations in a proficiency testing scheme (Holt et al, 2014). Immunoassays also presented bias when compared to HPLC results (Holt, Denny, Lee, & Johnston, 2001).…”

“…Complete and uniform extraction of the drug is important to obtain blood concentration values that are consistent and accurate for TDM (Holt et al, 2014). Sample preparation for TDM of immunosuppressant drugs is a challenge since it depends on understanding the physicochemical properties of the analytes, the environmental conditions and the matrix components of the sample (Zhang & Zhang, 2018).…”

Assessing Accuracy on the Front Lines: A Pragmatic Approach for Single-Donor Proficiency Testing

“…In the case of a method lacking a true peer group (including, for example, the overwhelming majority of mass spectrometry methods and other laboratory developed tests), even this limited type of comparison may not be possible. Additionally, when there are differences between peer groups comprising laboratories that use homogeneous systems (single manufacturer's instruments, calibrators, and reagents), the differences are often ascribed to lack of commutability (matrix effects) of the materials, although the differences may in fact be real and reflected in patient samples as well (3,4 ).…”

“…For tumor markers, we should report the method used along with the result values, and we should assist in reestablishing baselines for patients when methods are changed (16 ). For immunosuppressants, we should ensure that methods are harmonized on at least the parent compounds, and we should inform physicians that values, even on the basis of the same principle and from the same manufacturer, may not be interchangeable (4 ).…”