Assessing immunosuppressive drug concentrations in clinical practice

C H A P T E R

12 Assessing immunosuppressive drug concentrations in clinical practice Christoph Seger* Labormedizinisches zentrum Dr Risch, Buchs, Switzerland *Corresponding author.

Abstract Therapeutic drug monitoring of immunosuppressive drugs, namely, cyclosporine A, tacrolimus, sirolimus, everolimus, and mycophenolic acid, is an accepted measurement service that strongly supports transplantation medicine worldwide. During the past twenty years, ligand-binding assays lost their predominance, and liquid chromatography with tandem mass spectrometryebased analysis platforms gained importance. This transformation step is now finished, with both solutions in routine use. However, comparability between these methodologies is limited since traceability of the measurements to higher-order reference materials and reference standards is currently incompleteda frequent situation in drug monitoring and toxicology. The chapter will provide an overview of the development of this instrumental analysis field over the past twenty years.

12.1 Introduction Modern transplantation medicine would be unthinkable without the use of immunosuppressive drugs (ISDs). Soon after the introduction of cyclosporine A [1], the first modern-day ISD, into the standard care of transplanted patients [2], the field elevated and organ transplantation matured to a safe medical procedure [3e5]. From the early days on it became evident that therapeutic drug monitoring (TDM) must accompany treatment with ISDs since overdosing can lead to severe and life-threatening side effects (e.g., T-cell toxicity, hepatotoxicity, nephrotoxicity), and drug underexposure might end in graft function loss or rejection due to the recipient’s immune system attacking the graft tissue [6]. Confronted with this situation, the scientific community rapidly gathered, measurement procedures were developed, preanalytical terms were agreed upon, and pharmacokinetic/pharmacodynamic (PK/PD) parameters were established [7e9]. In 1987, a “Task Force on Cyclosporine Monitoring” under the leadership of Leslie M. Shaw published a summary of critical issues

Methods of Therapeutic Drug Monitoring including Pharmacogenetics https://doi.org/10.1016/B978-0-444-64066-6.00012-5

277

Ó 2020 Elsevier B.V. All rights reserved.

278

12. Assessing immunosuppressive drug concentrations in clinical practice

in cyclosporine A TDM, concluding with a set of recommendations. Among these were the central building blocks of modern-day immunosuppressive drug therapeutic drug monitoring (ISD-TDM): (1) whole blood is the matrix of choice, (2) measurement from EDTA whole blood, (3) use of a specific measurement procedure, (4) daily measurement during the postoperative care, (5) participation in accredited proficiency testing programs, and (6) TDM interpretation should be done in conjunction with other laboratory data and clinical considerations [10]. A first international workshop followed shortly thereafter (Hawk’s Cay Meeting on TDM of Cyclosporine) and a first international consensus document was issued [11]. This international approach to establish ISD-TDM on the safe ground of scientifically based guidance was maintained in the ensuing years with consensus meetings wrapping up latest developments in cyclosporine A TDM and expanding ISD-TDM to drugs introduced after cyclosporine A, namely, tacrolimus, sirolimus, everolimus, and mycophenolic acid [12e21,22]. Hence, by the time David Holt and Atholl Johnston, two major players in the scientific process described above, presented their overview on ISD-TDM in the first edition of this handbook issued in 2004 [23], PK/PD of the drugs had been already well established, and the specimen issue (whole blood is the specimen of choice for ISDs) for TDM routine was settled. Trough level measurements as a surrogate for systemic drug exposure (usually expressed by the area under the curve of a drug) were introduced and became generally accepted for most clinical situations [24]. Since then, several major modernization trends have been observed in clinical chemistry, two of them strongly influencing ISD-TDM. An ongoing trend toward laboratory service automation forced the in vitro diagnostics (IVD) industry to transfer immunological test applications such as radioimmunoassay (RIA) and enzyme immunoassay (EIA) to multianalyte highthroughput platforms. This transformation was not only a change of paradigm in endocrinology with ample advantages and horrendous pitfalls [25] but also in ISD-TDM where adherence to short turnaround times (TATs) based on stringent clinical needs of transplant patient care made automation attractive. With the introduction of the macrolide ISDs tacrolimus and sirolimus, the chromatographic analysis of ISDs needed to change from photometric UV detection to mass spectrometryebased detection units. Consequently, ISD-TDM has become a pioneer application field for liquid chromatographyemass spectrometry (LC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) in laboratory medicine. In the following sections, the status quo of this ongoing development will be presented. Wherever necessary, examples from past years will illustrate the development of this very special application field of instrumental analysis. For basic knowledge on the pharmacology of the discussed drugs [19,21,26e32], the development of LC-MS/MS in clinical chemistry [3336], and the advantages/disadvantages of ligand-binding assay technologies [37-39] the reader is referred to the selected review literature and the presentation of David Holt and Atholl Johnston in the first edition of this book [23].

12.1.1 Ligand-binding assays in ISD-TDM Currently, several ligand-binding assays (“immunoassays”) from various vendors are available for ISD-TDM [40,41] (Table 12.1). These technological realizations suffer from the general drawbacks of ligand-binding assays, including cross-reactivity of the employed antibody to metabolites of the drug (leading to an unclear measure and [42,43]), incomplete access

12.1 Introduction

TABLE 12.1

279

ISD-TDM analyte coverage sorted by ligand-binding assay type. For all five ISD analytes LC-MS/MS methods are available.

Method

Analyte

ACMIA

Cyclosporine, tacrolimus, sirolimus

CEDIA

Cyclosporine, MPA

CMIA

Cyclosporine, tacrolimus, sirolimus

DC-AEIA

Cyclosporine

ECLIA

Cyclosporine, tacrolimus, sirolimus, everolimus

EMIT

Cyclosporine, tacrolimus, sirolimus, MPA

IMPDH

MPA

PETINIA

MPA

QMS

Tacrolimus, everolimus

ACMIA, affinity columnemediated immunoassay; CEDIA, cloned enzyme donor immunoassay; CMIA, chemiluminescent microparticle immunoassay; DCLIA, direct chemiluminescence acridinium ester immunoassay; ECLIA, electrochemiluminescence immunoassay; EMIT, enzyme multiplied immunoassay technique; IMPDH, inosinmonophosphate-dehydrogenase; PETINIA, particle enhanced turbidimetric inhibition immunoassay; QMS, quantitative microsphere system.

to the erythrocyte or protein-bound analyte (leading to an unclear measured fraction), influence of the hematocrit, or the interference of heterophilic antibodies. In addition, for most assays, off-line hemolysis is mandatory as a sample preparation step, thus hampering swift sample throughput in an automated laboratory. This makes ISD TDM application disruptive and problematic in such settings; the situation is comparable to the analysis of folate in erythrocytes. All marketed ligand-binding assays have been evaluated against the assumed “gold standard” MS (realized as LC-MS/MS hyphenation), and none of these multicenter comparisons found an assay applicable for routine use. However, once in routine use, one or the other assay proved to be insufficient for routine application. For example, measurement results generated by the tacrolimus IMX/MEIA assay (since removed from the market) were strongly affected by the hematocrit of the sample [44e47]. On numerous occasions, false-positive results were reported with immunoassays based on the ACMIA test format, most likely due to problems with (heterophilic) antibodies of unclear origin [48e50]. This issue is ongoing and has obviously not yet been solved [51]. Latest additions to the ligand-binding assay portfolio are the CMIA format assays for tacrolimus, sirolimus, and cyclosporine A and the ECLIA format assays for tacrolimus, sirolimus, everolimus, and cyclosporine A. The CMIA tacrolimus assay introduced to the public in 2009 to replace the IMX/MEIA assay discussed above showed remarkable assay performance [52,53]. It outperformed several other immunoassays in terms of reproducibility as well as in sensitivity [54]. Tacrolimus levels down to approximately 1 ng/mL were measurable with very good data quality; in addition, a

280

12. Assessing immunosuppressive drug concentrations in clinical practice

must in combination therapy were lowered trough levels to reduce ISD side effects, e.g., nephrotoxicity [55,56]. This assay was the first immunological tacrolimus TDM platform that showed no bias to LC-MS/MS measurements and even outmatched this technology in terms of interlaboratory quality scores [57]. This successful assay placement was made possible by a complete redesign of the diagnostic testing antibody. A recombinant in vitro production format was chosen, and several cycles of “affinity maturation” took place to obtain a diagnostic protein matching the needs of in vitro testing [58,59]dan idea recently followed by others [60]. Another IVD company recently released novel single analyte assays for cyclosporine A [61,62], tacrolimus [63], sirolimus [64], and everolimus [65], utilizing the ECLIA immunoassay format. With the introduction of the everolimus assay, such TDM measurements were for the first time possible in a high-throughput assay format. The comparison to LCMS did show decent data quality; however, it must not be forgotten that everolimus TDM including a therapeutic target range suggestion issued by the drug producer has been primarily established by utilizing LCMS. Hence, care must be taken if immunoassays are utilized for everolimus TDM. For this analyte, fully validated LC-MS/MS methods are still considered the more appropriate assays [21]. On the other hand, it must not be overlooked that for cyclosporine A, tacrolimus, and sirolimus, immunological methods are the basis of target concentrations communicated in clinical standards of care documents. Hence, if LC-MS measurement services are established, the bias between immunological and LC-MS results must be evaluated and communicated to clinicians (the brain-to-brain loop concept of laboratory medicine [66,67]). A general problem of most immunological ISD-TDM solutions is related to a manual off-line sample preparation (pretreatment) step, which is necessary to release a fraction of the analyte from the erythrocyte membrane. Organic solvents are involved in this step (usually methanol/water mixtures) and only small series can be processed. Evaporation of the solvent must be prevented to avoid drug level overestimation [68].

12.1.2 Mass spectrometry assays in ISD-TDM At the beginning of the second decade of the 21st century, MS-based assays, usually realized in the LC-MS/MS format with quadrupole ion selection technology-based MS detectors, became a routine technology in TDM [69]. Consequently, it is not surprising that it also made a strong impact on ISD TDM due to its key advantages over ligand-binding assays, including multiplexing, meaning that several analytes could be measured within one assay, and very high selectivity, meaning that in small molecule analysis it is in principle possible by very simple technological/analytical means to avoid a quantitative contribution of metabolites or isobaric congener molecules present in the matrix to the analysis result [34,36]. However, as any other technology, LC-MS/MS has its technological limitations. If not properly respected, crossing the (often rather ill-defined) red line of a limitation may lead to serious problems in the technology application, including the generation of severe and unforeseeable irregular analytical errors [38]. The major source of such errors generally associated with MS is the possible presence of matrix effects (e.g., ion suppression or ion induction); this is particularly a risk when using the widely applied electrospray ionization (ESI) technology. In this context, influences by hydrophilic (e.g., salts) and lipophilic (e.g., phospholipids) matrix components are an issue and need to be targeted by appropriate countermeasures [70]. Here, achieving a high

12.1 Introduction

281

extraction efficacy and selectivity and striving for high resolution in the chromatographic domain (e.g., by the application of online SPE) as well as the use of stable isotope internal standards are strategies well-described and highly appreciated by the scientific community [71]. Further causes of error that can compromise measurement results and therefore must be addressed during method design and validation of LC-MS/MS procedures include insource fragmentation (e.g., demonstrated with the glucuronide metabolite of mycophenolic acid, MPAG [72]), interference with the internal standard transitions by drug metabolites (e.g., when using cyclosporine D (CsD) as internal standard for cyclosporine A (CsA) analysis [73]) or interference in drug analysis due to contamination of the internal standard used (e.g., analysis of sirolimus in a multiplex assay using 13C22H4-everolimus as the internal standard [74]). In addition, issues such as isotopic purity, cross-talk between MS/MS channels, and isotopic integrity should be considered when validating an LC-MS/MS method. It is strongly recommended that both clinicians and laboratory service staff be aware of the possible sources of error when interpreting results of the patients. Action plans must be in place to allow swift countermeasures if results are questioned. At the turn of the century, LC-MS/MS for ISD-TDM was in a premature state and was not deeply covered in prominent review articles as alternative technologies to immunoassays in clinical routine practice [75,76], although the first prominent scientific papersdincluding some from the diagnostic industrydwere presented in the last decade of the 20th century [77e85]. The first years of the 21st century saw a worldwide increase in novel LC-MS/MS ISD-TDM application papers, signaling a breakthrough of this technology. This breakthrough was made possible by several inventions leading to key technological improvements in (ESI) ion source design hyphenating liquid chromatography with MS. Only after providing stable measurement conditions, clinical MS with high demands on short TATs, long time measurement service stability, and rather high sample numbers became possible [47,86]. In ISD-TDM, the first key publications were presented [87e91]; at the end of the first decade, the process of establishing LC-MS/MS-based ISD-TDM could be called finalized with a multitude of individual lab developed tests presented to the scientific public [92e96]. The following years, however, observed still more dramatic changes for the measurement quality of this application since commercial calibrator and control materials were put into the market by at least two commercial providers and isotope labeled internal standards became available [97]. In addition, two vendors presented IVD-CE certified “kit” solutions applicable to qualified LC-MS/MS instruments [98]. Another vendor, based on the successful experiences on the clinical market with his LC-MS/MS instruments, even presented an IVD-CE certified LC-MS/MS platform to the public [99]. Recently, it was successfully proven that these harmonization efforts could lead to significant improvement of the analytical quality of LC-MS/MS in ISD-TDM [100]. With all these solutions at hand, increasing numbers of laboratories currently switch from immunoassay based ISD-TDM to LC-MS/MS supported services; this step is no longer seen as a major hurdle for clinical laboratories [101]. A survey undertaken in 2013 showed that most laboratories use LC-MS/MS assays, numbers reflected by data from proficiency testing schemes [40]. Regarding the quality of LC-MS/MS IDS assays, two recent publications impressively argued that beyond the mere claim of establishing a measurement method, clinical laboratory measurement services can indeed be offered with lab developed tests. Paul Taylor

282

12. Assessing immunosuppressive drug concentrations in clinical practice

summarized the experiences in his Australian laboratory in 2011 [102] and Olof Beck presented the European experience in 2016 [103]. Both authors could show convincingly that the routine quality of their assays in use matched that of conventional automated immunoassays in terms of TATs, robustness and reliability (analysis of down time), and clinical acceptance. Furthermore, they were also able to prove the long-time stability of their measurement services by analyzing their performance in external quality controls. Their findings were very consistent with a longitudinal analysis of proficiency testing data presented by David Holt in 2014 [104]. He showed over almost a decade that compared to a putative reference method operated by his laboratory, the LC-MS/MS group means (58e144 participating laboratories) on average did not deviate significantly from the target values.

12.1.3 Analytical quality in ISD-TDM Quality standards for ISD-TDM have been recently defined by an IATDMCT workgroup [40]. Summarizing, it can be stated that responsible state-of-the-art TDM can only be based on reliable measurement systems, the “TDM assays” [105] and that such assays can be either provided by industry or can be established locally (lab-developed tests). In any of these cases, such methods must not be assessed any differently from other quantitative measurements utilized to monitor endogenous analytes and xenobiotics in bioanalysis, food monitoring, or environmental analysis. The methodological basis for such assays is proper method design and thorough method validation. It was concluded that a variety of guidelines was currently available to define experiments leading to properly validated analytical methods; however, no specific guidance document for ISD-TDM was available. General recommendations coming closest to assay validation in clinical laboratory settings were summarized in several guidance documents issued by the Clinical & Laboratory Standards Institute (CLSI) but there were specific issues to be considered when implementing TDM services for immunosuppressive drugs (ISDs). For example, one must consider the adequacy of measurement ranges with steadily changing therapeutic schemes and TDM strategies; one must account for drug metabolites and coadministered drugs and must care about method consistency over time to assure long-term support of clinical services. Consequently, it is the responsibility of an individual analysis provider to ensure the quality of an analytical service by defining a guidance framework within the established quality management system. Within this regulative framework, guidelines published by both international scientific societies and governmental agencies (e.g., FDA, EMEA, CLSI, EURACHEM) can be adopted for the analysis of ISDs when considering specifics related to their TDM. In some of these documents, specific guidance on method validation of chromatographic methods (especially LC-MS/MS) as well as immunoassays has been provided. It must not be overlooked that the second pillar of analytical science is the proper use of analytical equipment. As any analytical method needs to be validated, an analytical instrument must be qualified. Only once qualified (e.g., by IQ/OQ procedures), such an instrument can be used as the technological basis of analytical assay development and validation. Finally, prior to utilization in an analytical service, a performance qualification proving the productivity and endurance of the desired instrument/assay combination under typical and extreme routine conditions must be carried out.

12.1 Introduction

283

It should not be forgotten that, for prolonged routine operation with changing personnel and limited long-term availability of hardware/software components or reagents, risks may arise that should be taken care of by a proper risk analysis.

12.1.4 Traceability in ISD-TDM The applicability and reliability of analytical figures generated by laboratories is strongly linked with data qualitydtheir accuracy. This general remark holds true for any kind of measurement service and is not limited to clinically relevant entities such as the drugs discussed in the context of this paper. Laboratory medicine adopted relatively early the general metrological concept of traceability [106,107] and established a tight cooperation with national metrological institutes. By founding the Joint Committee for Traceability in Laboratory Medicine (JCTLM) located at the International Bureau of Weights and Measures (BIPM) [108], chemical and biological entities in laboratory medicine have been raised to the same level of international reasoning and care as classical SI units for measuring time, weight, and lengths. If individual laboratory units used the same test principle, e.g., an automated immunoassay, traceability of locally applied calibration measurement to an “industrial master calibration” is usually assured and guaranteed by the assay vendor. The vendor (e.g., operating under FDA clearance or within the framework of an obtained IVD-CE certification) is responsible for the trueness (¼ lack of bias) of the local calibration to this master calibration. The expected assay precision is also stated by the assay producer, and local deviations to the given numbers must be carefully monitored, since they increase the total error of an assay. If such deviations exceed (definable) thresholds, the local laboratory is obliged to hold the assay vendor responsible for taking corrective actions (e.g., running an additional service, changing a pipetting unit, etc.) to prevent the occurrence of irregular analytical errors [38]. If a laboratory has decided to develop an “in-house assay” (¼ lab developed assay”, LDT) the responsibility for maintaining the trueness and precision of a measurement service is completely within the responsibility of the individual laboratory, hence imposing an increased risk of failure [36]. This risk can be minimized if at least the trueness of the assay is kept under control by using unified (commercial) calibrator materials. It has been impressively shown for 25-OH vitamin D [109] and tacrolimus [100] that this approach reduces the risk of interlaboratory imprecision, which in reverse conclusion improves the comparability of patient results obtained at individual points of laboratory service. However, in ISD-TDM assay traceability is currently hardly realized. Besides tacrolimus, efforts to establish assay comparability are hardly present in the scientific community or the IVD industry. Hence this analyte is taken as example to sketch the development of this demanding task. The tacrolimus TDM market is currently shared between with five FDA-cleared immunoassay realizations (approx. 55% of total with one major provider holding 2/3 of this share) and LC-MS/MS installations of different origin (majority of assays lab developed, two IVD-CE certified kit systems available) [40]. With the analytical limitations described further above, one can easily assume that the trueness between these measurement platform realizations is limited. Proficiency data impressively supported this assumption (Fig. 12.1), hence making it necessary to expand the traceability of individual tacrolimus measurement services beyond individual industrial or commercial calibrator systems.

284

12. Assessing immunosuppressive drug concentrations in clinical practice

30

10 0

EMIT

ACMIA

ECLIA

-20

CMIA

-10 LCMS/MS

bias to comparator (%)

20

-30

FIGURE 12.1

Proficiency testingebased tacrolimus TDM bias analysis of ISD-TDM routine measurements. Data from 18 patient samples distributed by the UKNEQAS PT scheme (www.bioanalysis.co.uk) over a timeframe of 5 years (60 challenges) were analyzed. Ligand-binding assay results were compared to the LCMS group mean, the LCMS group was compared against the target value issued by the PT scheme provider. Mean analyte concentration for the LCMS group: 7.7 mg/L (target value 7.5 mg/L). Average participant number in the groups: LCMS 180, CLIA 155, ECLIA 20, ACMIA 30, EMIT 20.

Some years ago, LGC, a National Measurement Laboratory (NML) in the United Kingdom, took up this challenge and presented two certified reference materials to the public: ERM-DA110a, a tacrolimus-containing whole blood matrix in 2014 (secondary higher order reference material) and in 2017, ERM-AC022a, which is pure tacrolimus (neat substance, primary higher order reference material). ERM-AC022a was characterized by quantitative NMR, a methodology that is a must for characterizing pure substances or mixtures in at least the same analytical quality as LC-UV or LC-MS/MS [110e113]. For ERM-DA110a, it is unfortunately not clear to the scientific public which reference method was applied for value assignment, since the primary reference method was not disclosed as it had been in other fields, e.g., for steroid hormone measurements [114,115]. However, ERM-DA110a was listed by the JCTLM, implying that the responsible JCTLM workgroup reviewed the reports associated with ERM-DA110a and reasoned that they were in accordance with the JCTLM regulationsdincluding main regulatory and scientific issues. Regarding measurement methods in the entire field of ISD-TDM currently only one peer-reviewed (candidate) reference method has been published for cyclosporine A [116]. Regarding JCTLM listing, as of now no other ISD reference material has been listed and no reference method has been cleared by the board. Within the Scientific Division (SD) of the IFCC (International Federation of Clinical Chemistry), a workgroup (WG-ID) [117] was founded in 2018 to focus activities in this field, including the generation of reference materials and the placement of appropriate reference procedures for ISDs including tacrolimus.

12.2 Conclusions Currently, ISD-TDM is a globally accepted measurement service strongly supporting transplantation medicine. Within the past twenty years, ligand-binding assays lost predominance

References

285

and LC-MS/MS-based analysis platforms gained importance. Traceability of the measurements to higher order reference materials and reference standards is still not completely given, but this a quite frequent situation in drug monitoring and toxicology.

References [1] B.D. Kahan, Cyclosporine, N. Engl. J. Med. 321 (1989) 1725e1738. [2] R.Y. Calne, K. Rolles, D.J. White, S. Thiru, D.B. Evans, P. McMaster, D.C. Dunn, G.N. Craddock, R.G. Henderson, S. Aziz, P. Lewis, Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers, Lancet 8151 (1979) 1033e1036. [3] B.D. Kahan, Forty years of publication of transplantation proceedings e the second decade: the cyclosporine revolution, Transplant. Proc. 41 (2009) 1423e1437. [4] C.F. Barker, J.F. Markmann, Historical overview of transplantation, Cold Spring Harb. Perspect. Med. 3 (2013) a014977. [5] K.R. Schumacher, R.J. Gajarski, Postoperative care of the transplanted patient, Curr. Cardiol. Rev. 7 (2011) 110e122. [6] B.D. Kahan, Cosmas and Damian in the 20th century, N. Engl. J. Med. 305 (1981) 280e281. [7] B.D. Kahan, Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters, Transplantation 40 (1985) 457e476. [8] G.J. Burckart, D.M. Canafax, G.C. Yee, Cyclosporine monitoring, Drug Intell. Clin. Pharm. 20 (1986) 649e652. [9] V. Warty, S. Zuckerman, R. Venkataramanan, J. Lever, J. Chao, T. Mckaveney, J. Fung, T. Starzl, Tacrolimus analysis: a comparison of different methods and matrices, Ther. Drug Monit. 17 (1995) 159e167. [10] L.M. Shaw, L. Bowers, L. Demers, D. Freeman, T. Moyer, A. Sanghvi, H. Seltman, R. Venkataramanan, Critical issues in cyclosporine monitoring: report of the task force on cyclosporine monitoring, Clin. Chem. 33 (1987) 1269e1288. [11] B.D. Kahan, L.M. Shaw, D. Holt, J. Grevel, A. Johnston, Consensus document: Hawk’s Cay meeting on therapeutic drug monitoring of cyclosporine, Clin. Chem. 36 (1990) 1510e1516. [12] M. Oellerich, V.W. Armstrong, B. Kahan, L.M. Shaw, D.W. Holt, R. Yatscoff, A. Lindholm, P. Halloran, K. Gallicano, K. Wonigeit, E. Scheutz, H. Schran, T. Annesley, Lake Louise consensus meeting on cyclosporin monitoring in organ transplantation: report of the consensus panel, Ther. Drug Monit. 17 (1995) 642e654. [13] W.J. Jusko, A.W. Thomson, J. Fung, P. McMaster, S.H. Wong, E. Zylber-Katz, U. Christians, M. Winkler, W.E. Fitzsimmons, R. Lieberman, Consensus document: therapeutic monitoring of tacrolimus (FK-506), Ther. Drug Monit. 17 (1995) 606e614. [14] R.W. Yatscoff, R. Boeckx, D.W. : Holt, B.D. Kahan, D.F. LeGatt, S. Sehgal, S.J. Soldin, K. Napoli, C. Stiller, Consensus guidelines for therapeutic drug monitoring of rapamycin: report of the consensus panel, Ther. Drug Monit. 17 (1995) 676e680. [15] L.M. Shaw, A. Nicholls, M. Hale, V.W. Armstrong, M. Oellerich, R. Yatscoff, R.E. Morris, D.W. Holt, R. Venkataramanan, J. Haley, P. Halloran, R. Ettenger, P. Keown, R.G. Morris, Therapeutic monitoring of mycophenolic acid. A consensus panel report, Clin. Biochem. 31 (1998) 317e322. [16] M. Oellerich, V.W. Armstrong, E. Schutz, L.M. Shaw, Therapeutic drug monitoring of cyclosporine and tacrolimus. Update on Lake Louise consensus conference on cyclosporin and tacrolimus, Clin. Biochem. 31 (1998) 309e316. [17] D.W. Holt, V.W. Armstrong, A. Griesmacher, R.G. Morris, K.L. Napoli, L.M. Shaw, International federation of clinical chemistry/international association of therapeutic drug monitoring and clinical toxicology working group on immunosuppressive drugs monitoring, Ther. Drug Monit. 24 (2002) 59e67. [18] R.G. Morris, D.W. Holt, V.W. Armstrong, A. Griesmacher, K.L. Napoli, L.M. Shaw, IFCC/IATDMCT Joint Working Group. Analytic aspects of cyclosporine monitoring, on behalf of the IFCC/IATDMCT Joint Working Group, Ther. Drug Monit. 26 (2004) 227e230. [19] P. Wallemacq, V.W. Armstrong, M. Brunet, V. Haufroid, D.W. Holt, A. Johnston, D. Kuypers, Y. Le Meur, P. Marquet, M. Oellerich, E. Thervet, B. Toenshoff, N. Undre, L.T. Weber, I.S. Westley, M. Mourad, Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference, Ther. Drug Monit. 31 (2009) 139e152.

286

12. Assessing immunosuppressive drug concentrations in clinical practice

[20] D.R. Kuypers, Y. Le Meur, M. Cantarovich, M.J. Tredger, S.E. Tett, D. Cattaneo, B. Tönshoff, D.W. Holt, J. Chapman, T. van Gelder, Transplantation Society (TTS) Consensus Group on TDM of MPA. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation, Clin. J. Am. Soc. Nephrol. 5 (2010) 341e358. [21] M. Shipkova, D.A. Hesselink, D.W. Holt, E.M. Billaud, T. van Gelder, P.K. Kunicki, M. Brunet, K. Budde, M.J. Barten, P. De Simone, E. Wieland, O.M. Lopez, S. Masuda, C. Seger, N. Picard, M. Oellerich, L.J. Langman, P. Wallemacq, R.G. Morris, C. Thompson, P. Marquet, Therapeutic drug monitoring of everolimus: a consensus report, Ther. Drug Monit. 28 (2016) 143e169. [22] M. Brunet, T. van Gelder, A. Åsberg, V. Haufroid, D. Hesselink, L. Langman, F. Lemaitre, P. Marquet, C. Seger, M. Shipkova, A. Vinks, P. Wallemacq, E.Wieland, J.B. Woillard, M.J. Barten, K. Budde, H. Colom, M.T.Dieterlen, L. Elens, K.L. Johnson-Davis, P.K. Kunicki, I. MacPhee, S.Masuda, B.S. Mathew, O. Millán, T. Mizuno, D.A.R. Moes, C. Monchaud, O.Noceti, T. Pawinski, N. Picard, R. van Schaik, C. Sommerer, N.T. Vethe, B. de Winter, U. Christians, S. Bergan, Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report, Ther. Drug Monit 41 (2019) 261e307. [23] D.W. Holt, A. Johnston, Monitoring of immunusuppressive drugs, in: G. Hempel (Ed.), Handbook of Analytical Separations, Elsevier, Oxford, 2004, pp. 271e294. [24] R.G. Morris, Cyclosporin therapeutic drug monitoring-an established service revisited, Clin. Biochem. Rev. 24 (2003) 33e46. [25] A.M. Jones, J.W. Honour, Unusual results from immunoassays and the role of the clinical endocrinologist, Clin. Endocrinol. 64 (2006) 234e244. [26] C.J. Dunn, A.J. Wagstaff, C.M. Perry, G.L. Plosker, K.L. Goa, Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral) in organ transplantation, Drugs 61 (2001) 1957e2016. [27] J.M. Barbarino, C.E. Saatz, R. Venkataramanan, T.E. Klein, R.B. Altman, PharmGKB summary: cyclosporine and tacrolimus pathways, Pharmacogenetics Genom. 23 (2013) 563e585. [28] L.J. Scott, K. McKeage, S.J. Keam, G.L. Plosker, Tacrolimus: a further update of its use in the management of organ transplantation, Drugs 63 (2003) 1247e1297. [29] L.M. Andrews, Y. Li, B.C.M. De Winter, Y.Y. Shi, C.C. Baan, T. van Gelder, D.A. Hesselink, Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients, Expert Opin. Drug Metabol. Toxicol. 13 (2017) 1225e1236. [30] C. Dunn, K.F. Croom, Everolimus: a review of its use in renal and cardiac transplantation, Drugs 66 (2006) 547e570. [31] K. Mahalati, B.D. Kahan, Clinical pharmacokinetics of sirolimus, Clin. Pharmacokinet. 40 (2001) 573e585. [32] B. Fulton, A. Markham, Mycophenolate mofetil. A review of its pharmacodynamics and pharmacokinetic properties and clinical efficacy in renal transplantation, Drugs 51 (1996) 278e298. [33] J.W. Honour, Development and validation of a quantitative assay based on tandem mass spectrometry, Ann. Clin. Biochem. 48 (2011) 97e111. [34] M. Vogeser, C. Seger, Pitfalls associated with the use of liquid chromatography-tandem mass spectrometry in the clinical laboratory, Clin. Chem 56 (2010) 1234e1244. [35] J.E. Adaway, B.G. Keevil, L.J. Owen, Liquid chromatography tandem mass spectrometry in the clinical laboratory, Ann. Clin. Biochem 52 (2015) 18e38. [36] M. Vogeser, C. Seger, Quality management in clinical application of mass spectrometry measurement systems, Clin. Biochem 49 (2016) 947e954. [37] A.E. Taylor, B. Keevil, I.T. Huhtaniemi, Mass spectrometry and immunoassay: how to measure steroid hormones today and tomorrow, Eur. J. Endocrinol. 173 (2015) D1eD12. [38] M. Vogeser, C. Seger, Irregular analytical errors in diagnostic testing e a novel concept, Clin. Chem. Lab. Med. 56 (2018) 386e396. [39] J.W. Honour, Steroid assays in paediatric endocrinology, J. Clin. Res. Pediatr. Endocrinol. 2 (2010) 1e16. [40] C. Seger, M. Shipkova, U. Christians, E.M. Billaud, P. Wang, D.W. Holt, M. Brunet, P.K. Kunicki, T. Pawinski, L.J. Langman, P. Marquet, M. Oellerich, E. Wieland, P. Wallemacq, Assuring the proper analytical performance of measurement procedures for immunosuppressive drug concentrations in clinical practice: recommendations of the international association of therapeutic drug monitoring and clinical toxicology immunosuppressive drug scientific committee, Ther. Drug Monit. 38 (2016) 170e189.

References

287

[41] A. Mika, P. Stepnowski P, Current methods of the analysis of immunosuppressive agents in clinical materials: a review, J. Pharm. Biomed. Anal. 127 (2016) 207e231. [42] E. Schütz, D. Svinarov, M. Shipkova, P.D. Niedmann, V.W. Armstrong, E. Wieland, M. Oellerich, Cyclosporin whole blood immunoassays (AxSYM, CEDIA, and Emit): a critical overview of performance characteristics and comparison with HPLC, Clin. Chem. 44 (1998) 2158e2164. [43] W. Steimer, Performance and specificity of monoclonal immunoassays for cyclosporine monitoring: how specific is specific? Clin. Chem. 45 (1999) 371e381. [44] K.L. Napoli, Is microparticle enzyme-linked immunoassay (MEIA) reliable for use in tacrolimus TDM? Comparison of MEIA to liquid chromatography with mass spectrometric detection using longitudinal trough samples from transplant recipients, Ther. Drug Monit. 28 (2006) 491e504. [45] N.W. Brown, C.E. Gonde, J.E. Adams, J.M. Tredger, Low hematocrit and serum albumin concentrations underlie the overestimation of tacrolimus concentrations by microparticle enzyme immunoassay versus liquid chromatography-tandem mass spectrometry, Clin. Chem. 51 (2005) 586e592. [46] C. Seger, K. Tentschert, A. Griesmacher, Evaluating performance limitations of a tacrolimus immunoassay by comparison with a HPLC-MS/MS platform, Ther. Drug Monit. 29 (2007) 509. [47] C. Seger, M. Vogeser, Immunosuppressant drug monitoring e a routine undertaking? J. Lab. Med. 34 (2010) 117e128. [48] J. Morelle, P. Wallemacq, O. van Caeneghem, E. Goffin, Clinically unexpected cyclosporine levels using the ACMIA method on the RXL dimension analyser, Nephrol. Dial. Transplant. 26 (2011) 1428e1431. [49] J. Hermida, J.C. Tutor, Falsely increased blood tacrolimus concentrations using the ACMIA assay due to circulating endogenous antibodies in a liver transplant recipient: a tentative approach to obtaining reliable results, Ther. Drug Monit. 31 (2009) 269e272. [50] A. Peter, M. Shipkova, E. Wieland, E. Schleicher, I. Müller, Increased cyclosporine concentrations in the absence of cyclosporine administration, Clin. Chem. 57 (2011) 670e673. [51] M. Kono, J. Hasegawa, H. Ogawa, K. Yoshikawa, A. Ishiwatari, S. Wakai, K. Tanabe, H. Shirakawa, False elevation of the blood tacrolimus concentration, as assessed by an affinity column-mediated immunoassay (ACMIA), led to acute T cell-mediated rejection after kidney transplantation: a case report, Intern. Med. 57 (2018) 1265e1268. [52] P. Wallemacq, J.S. Goffinet, S. O’Morchoe, T. Rosiere, G.T. Maine, M. Labalette, G. Aimo, D. Dickson, E. Schmidt, R. Schwinzer, R.W. Schmid, Multi-site analytical evaluation of the Abbott Architect tacrolimus assay, Ther. Drug Monit. 31 (2009) 198e204. [53] B.K. De, E. Jimenez, S. De, J.C. Sawyer, G.A. McMillin, Analytical performance characteristics of the Abbott Architect i2000 Tacrolimus assay; comparisons with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Abbott IMx methods, Clin. Chim. Acta 410 (2009) 25e30. [54] S. Amann, T.S. Parker, D.M. Levine, Evaluation of 2 immunoassays for monitoring low blood levels of tacrolimus, Ther. Drug Monit. 31 (2009) 273e276. [55] H. Ekberg, H. Tedesco-Silva, A. Demirbas, S. Vítko, B. Nashan, A. Gürkan, R. Margreiter, C. Hugo, J.M. Grinyo, U. Frei, Y. Vanrenterghem, P. Daloze, P.F. Halloran, ELITE-Symphony Study, Reduced exposure to calcineurin inhibitors in renal transplantation, N. Engl. J. Med. 357 (2007) 2562e2575. [56] H. Ekberg, T. van Gelder, B. Kaplan, C. Bernasconi, Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation, Transplantation 92 (2011) 82e87. [57] D.M. Levine, G.T. Maine, D.A. Armbruster, C. Mussell, C. Buchholz, G. O’Connor, V. Tuck, A. Johnston, D.W. Holt, The need for standardization of tacrolimus assays, Clin. Chem. 57 (2011) 1739e1747. [58] V. Gounden, S.J. Soldin, Tacrolimus measurement: building a better immunoassay, Clin. Chem. 60 (2014) 575e576. [59] R.W. Siegel, W. Baugher, T. Rahn, S. Drengler, J. Tyner, Affinity maturation of tacrolimus antibody for improved immunoassay performance, Clin. Chem. 54 (2008) 1008e1017. [60] T.Q. Wei, Y.F. Zheng, M. Dubowy, M. Sharma, Sandwich assay for tacrolimus using 2 antitacrolimus antibodies, Clin. Chem. 60 (2014) 621e630. [61] M. Vogeser, M. Shipkova, R. Rigo-Bonnin, P. Wallemacq, M. Orth, M. Widmann, A.G. Verstraete, Multicenter analytical evaluation of the automated electrochemiluminescence immunoassay for cyclosporine, Ther. Drug Monit. 36 (2014) 640e650.

288

12. Assessing immunosuppressive drug concentrations in clinical practice

[62] A.W.S. Fung, M.J. Knauer, I.M. Blasutig, D.A. Colantonio, V. Kulasingam, Evaluation of electrochemiluminescence immunoassays for immunosuppressive drugs on the Roche cobas e411 analyzer, F1000Res. 6 (2017) 1832. [63] M. Shipkova, M. Vogeser, P.A. Ramos, A.G. Verstraete, M. Orth, C. Schneider, P. Wallemacq P, Multi-center analytical evaluation of a novel automated tacrolimus immunoassay, Clin. Biochem. 47 (2014) 1069e1077. [64] V. Stove, P.A. Ramos, P. Wallemacq, M. Vogeser, A. Schuetzenmeister, C. Schmiedel, M. Shipkova, Measurement of sirolimus concentrations in human blood using an automated electrochemiluminescence immunoassay (ECLIA): a multicenter evaluation, Clin. Chem. Lab. Med. 56 (2018), 764-755. [65] A.G. Verstraete, R. Rigo-Bonnin, P. Wallemacq, M. Vogeser, A. Schuetzenmeister, C. Schmiedel, M. Shipkova, Multicenter evaluation of a new electrochemiluminescence immunoassay for everolimus concentrations in whole blood, Ther. Drug Monit. 40 (2018) 59e68. [66] G.D. Lundberg, Adding outcome as the 10th step in the brain-to-brain laboratory test loop, Am. J. Clin. Pathol. 141 (2014) 767e769. [67] M. Plebani, M. Laposata, G.D. Lundberg, The brain-to-brain loop concept for laboratory testing 40 years after its introduction, Am. J. Clin. Pathol. 136 (2011) 829e833. [68] S. Albeiroti, M.O. Alberti, V. Buggs, G. Swartz, A.W. Butch, J.C. Drees, K.A. Kelly, Evaluation of 2 batched pretreatment systems for the measurement of whole blood tacrolimus on the ARCHITECT immunoassay analyzer, Lab. Med. 47 (2016) 268e274. [69] M. Shipkova, D. Svinarov, LC-MS/MS as a tool for TDM services: where are we? Clin. Biochem. 49 (2016) 1009e1023. [70] A. van Eeckhaut, K. Lanckmans, S. Sarre, I. Smolders, Y. Michotte, Validation of bioanalytical LC-MS/MS assays: evaluation of matrix effects, J. Chromatogr. B 877 (2009) 2198e2207. [71] P.J. Taylor, Matrix effects: the Achilles heel of quantitative high-performance liquid chromatographyelectrospray-tandem mass spectrometry, Clin. Biochem. 38 (2005) 328e334. [72] M. Vogeser, R. Zachoval, U. Spöhrer, K. Jacob, Potential lack of specificity using electrospray tandem-mass spectrometry for the analysis of mycophenolic acid in serum, Ther. Drug Monit. 23 (2001) 722e724. [73] M. Vogeser, U. Spöhrer, Pitfall in the high-throughput quantification of whole blood cyclosporin A using liquid chromatography-tandem mass spectrometry, Clin. Chem. Lab. Med. 43 (2005) 400e402. [74] P.E. Morgan, N.W. Brown, J.M. Tredger, A direct method for the measurement of everolimus and sirolimus in whole blood by LC-MS/MS using an isotopic everolimus internal standard, Ther. Drug Monit. 36 (2014) 358e365. [75] A. Johnston, D.W. Holt, Therpeutic drug monitoring of immunosuppressant drugs, Br. J. Clin. Pharmacol. 47 (1999) 339e350. [76] V.W. Armstrong, Principles and practice of monitoring immunosuppressive drugs, J. Lab. Med. 26 (2002) 27e36. [77] G.I. Kirchner, C. Vidal, W. Jacobsen, A. Franzke, K. Hallensleben, U. Christians, K.F. Seweing, Simultaneous on-line extraction and analysis of sirolimus (rapamycin) and ciclosporin in blood by liquid chromatography e electrospray mass spectrometry, J. Chromatogr. B 721 (1999) 285e294. [78] A.K. Gonschior, U. Christians, F. Braun, M. Winkler, A. Linck, J. Baumann, K.F. Sewing, Measurement of blood concentrations of FK506 (tacrolimus) and its metabolites in seven liver graft patients after the first dose by h.p.l.c.-MS and microparticle enzyme immunoassay (MEIA), Br. J. Clin. Pharmacol. 38 (1994) 567e571. [79] J. Simpson, Q. Zhang, P. Ozaeta, H.I. Aboleneen, A specific method for the measurement of cyclosporin A in human whole blood by liquid chromatography-tandem mass spectrometry, Ther. Drug Monit. 20 (1998) 294e300. [80] Q. Zhang, J. Simpson, H.I. Aboleneen, A specific method for the measurement of tacrolimus in human whole blood by liquid chromatography/tandem mass spectrometry, Ther. Drug Monit. 19 (1997) 470e476. [81] P.J. Taylor, A. Jones, G.A. Balderson, S.V. Lynch, R.L. Norris, S.M. Pond, Sensitive, specific quantitative analysis of tacrolimus (FK506) in blood by liquid chromatography-electrospray tandem mass spectrometry, Clin. Chem. 42 (1996) 279e285. [82] P.J. Taylor, C.E. Jones, P.T. Martin, S.V. Lynch, A.G. Johnson, S.M. Pond, Microscale high-performance liquid chromatography-electrospray tandem mass spectrometry assay for cyclosporin A in blood, J. Chromatogr. B 705 (1998) 289e294.

References

289

[83] P.J. Taylor, A.G. Johnson, Quantitative analysis of sirolimus (Rapamycin) in blood by high-performance liquid chromatography-electrospray tandem mass spectrometry, J. Chromatogr. B 718 (1998) 251e257. [84] F. Streit, U. Christians, H.M. Schiebel, K.L. Napoli, L. Ernst, A.: Linck, B.D. Kahan, K.F.: Sewing, Sensitive and specific quantification of sirolimus (rapamycin) and its metabolites in blood of kidney graft recipients by HPLC/electrospray-mass spectrometry, Clin. Chem. 42 (1996) 1417e1425. [85] G.I. Kirchner, C. Vidal, W. Jacobsen, A. Franzke, K. Hallensleben, U. Christians, K.F. Sewing, Simultaneous online extraction and analysis of sirolimus (rapamycin) and ciclosporin in blood by liquid chromatographyelectrospray mass spectrometry, J. Chromatogr. B 22 (1999) 285e994. [86] M. Vogeser, C. Seger, A decade of HPLC-MS/MS in the routine clinical laboratory e goals for further developments, Clin. Biochem. 41 (2008) 649e662. [87] A. Volosov, K.L. Napoli, S.J. Soldin, Simultaneous simple and fast quantification of three major immunosuppressants by liquid chromatography e tandem mass-spectrometry, Clin. Biochem. 34 (2001) 285e290. [88] C.E. Staatz, P.J. Taylor, S.E. Tett, Comparison of an ELISA and an LC/MS/MS method for measuring tacrolimus concentrations and making dosage decisions in transplant recipients, Ther. Drug Monit. 24 (2002) 607e615. [89] F. Streit, V.W. Armstrong, M. Oellerich, Rapid liquid chromatography e tandem mass spectrometry routine method for simultaneous determination of sirolimus, everolimus, tacrolimus, and cyclosporin A in whole blood, Clin. Chem. 48 (2002) 955e958. [90] M. Deters, G. Kirchner, K. Resch, V. Kaever, Simultaneous quantification of sirolimus, everolimus, tacrolimus and cyclosporine by liquid chromatographyemass spectrometry (LCeMS), Clin. Chem. Lab. Med. 40 (2002) 285e292. [91] U. Ceglarek, J. Lembcke, G.M. Fiedler, M. Werner, H. Witzigmann, J.P. Hauss, J. Thiery, Rapid simultaneous quantification of immunosuppressants in transplant patients by turbulent flow chromatography combined with tandem mass spectrometry, Clin. Chim. Acta 346 (2004) 181e190. [92] C. Seger, K. Tentschert, W. Stöggl, A. Griesmacher, S.L. Ramsay, A rapid HPLC-MS/MS method for the simultaneous quantification of cyclosporine A, tacrolimus, sirolimus and everolimus in human blood samples, Nat. Protoc. 4 (2009) 526e534. [93] R.A. Koster, E.C. Dijkers, D.R. Uges, Robust, high-throughput LC-MS/MS method for therapeutic drug monitoring of cyclosporine, tacrolimus, everolimus, and sirolimus in whole blood, Ther. Drug Monit. 31 (2009) 116e125. [94] M. Marinova, C. Artusi, L. Brugnolo, G. Antonelli, M. Zaninotto, M. Plebani, Immunosuppressant therapeutic drug monitoring by LC-MS/MS: workflow optimization through automated processing of whole blood samples, Clin. Biochem. 46 (2013) 1723e1727. [95] A. Meinitzer, G. Gartner, S. Pilz, M. Stettin, Ultra fast liquid chromatography-tandem mass spectrometry routine method for simultaneous determination of cyclosporin A, tacrolimus, sirolimus, and everolimus in whole blood using deuterated internal standards for cyclosporin A and everolimus, Ther. Drug Monit. 32 (2010) 61e66. [96] M. Ivanova, C. Artusi, G. Polo, M. Zaninotto, M. Plebani, High-throughput LC-MS/MS method for monitoring sirolimus and everolimus in the routine clinical laboratory, Clin. Chem. Lab. Med. 49 (2011) 1151e1158. [97] H. Valbuena, M. Shipkova, S.M. Kliesch, S. Müller, E. Wieland, Comparing the effect of isotopically labeled or structural analog internal standards on the performance of a LC-MS/MS method to determine ciclosporin A, everolimus, sirolimus and tacrolimus in whole blood, Clin. Chem. Lab. Med. 54 (2016) 437e446. [98] S. Becker, J. Thiery, U. Ceglarek, Evaluation of a novel commercial assay for the determination of cyclosporine A, tacrolimus, sirolimus, and everolimus by liquid chromatography-tandem mass spectrometric assay, Ther. Drug Monit. 35 (2013) 129e132. [99] A. Saitman, I.G. Metushi, D.S. Mason, R.L. Fitzgerald, Evaluation of the waters MassTrak LC-MS/MS assay for tacrolimus and a comparison to the Abbott Architect immunoassay, Ther. Drug Monit. 38 (2016) 300e304. [100] T.M. Annesley, D.A. McKeown, D.W. Holt, C. Mussell, E. Champarnaud, L. Harter, L.J. Calton, D.S. Mason, Standardization of LC-MS for therapeutic drug monitoring of tacrolimus, Clin. Chem. 59 (2013) 1630e1637. [101] P.O. Hetu, R. Robitaille, B. Vinet, Successful and cost-efficient replacement of immunoassays by tandem mass spectrometry for the quantification of immunosuppressants in the clinical laboratory, J. Chromatogr. B 883e884 (2012) 95e101.

290

12. Assessing immunosuppressive drug concentrations in clinical practice

[102] P.J. Taylor, M.E. Franklin, C.H. Tai, P.I. Pillans, Therapeutic drug monitoring of tacrolimus by liquid chromatography-tandem mass spectrometry: is it truly a routine test? J. Chromatogr. B 883e884 (2012) 108e112. [103] A. Pohanka, S. Rosenborg, J.D. Lindh, O. Beck, Experiences from using LC-MS/MS for analysis of immunosuppressive drugs in a TDM service, Clin. Biochem. 49 (2016) 1024e1031. [104] D.W. Holt, D.A. Mandelbrot, M.A. Tortorici, J.M. Korth-Bradley, D. Sierka, D.I. Levy, S. See Tai, G.L. Horwitz, Long-term evaluation of analytical methods used in sirolimus therapeutic drug monitoring, Clin. Transplant. 28 (2014) 243e251. [105] L.D. Bowers, Analytical goals in therapeutic drug monitoring, Clin. Chem. 44 (1998) 375e380. [106] L. Siekmann, Metrological traceability e a concept for standardization in laboratory medicine, Clin. Chem. Lab. Med. 51 (2013) 953e957. [107] H.W. Vesper, G.L. Myers, W.G. Miller, Current practices and challenges in the standardization and harmonization of clinical laboratory tests, Am. J. Clin. Nutr. 104 (2016) 907Se912S. [108] G.R. Jones, C. Jackson, The Joint Committee for Traceability in Laboratory Medicine (JCTLM) e its history and operation, Clin. Chim. Acta 453 (2016) 86e94. [109] A.M. Yates, A. Bowron, L. Calton, J. Heynes, H. Field, S. Rainbow, B. Keevil, Interlaboratory variation in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 is significantly improved if common calibration material is used, Clin. Chem. 54 (2008), 2082-1084. [110] M. Weber, C. Hellriegel, A. Rueck, J. Wuethrich, P. Jenks, Using high-performance 1H NMR (HP-qNMRÒ) for the certification of organic reference materials under accreditation guidelines e describing the overall process with focus on homogeneity and stability assessment, J. Pharm. Biomed. Anal. 93 (2014) 102e110. [111] T. Saito, T. Ihara, M. Koike, S. Kinugasa, Y. Fujimine, K. Nose, T. Hirai, A new traceability scheme for the development of nternational system-traceable persistent organic pollutant reference materials by quantitative nuclear magnetic resonance, Accred Qual. Assur. 14 (2009) 79e86. [112] G.F. Pauli, S.N. Chen, C. Simmler, D.C. Lankin, T. Gödecke, B.U. Jaki, J.B. Friesen, J.B. McAlpine, J.G. Napolitano, Importance of purity evaluation and the potential of quantitative 1H NMR as a purity assay, J. Med. Chem. 57 (2014) 9220e9231. [113] A. Cheilari, S. Sturm, D. Intelmann, C. Seger, H. Stuppner, Head-to-Head comparison of ultra-highperformance liquid chromatography with diode array detection versus quantitative nuclear magnetic resonance for the quantitative analysis of the silymarin complex in silybum marianum fruit extracts, J. Agric. Food Chem. 64 (2016) 1618e1626. [114] J.C. Botelho, A. Ribera, H.C. Cooper, H.W. Vesper, Evaluation of an isotope dilution HPLC tandem mass spectrometry candidate reference measurement procedure for total 17-b estradiol in human serum, Anal. Chem. 88 (2016) 11123e11129. [115] J.C. Botelho, C. Shacklady, H.C. Cooper, S.S. Tai, K. van Uytfanghe, L.M. Thienpont, H.W. Vesper HW, Isotope-dilution liquid chromatography-tandem mass spectrometry candidate reference method for total testosterone in human serum, Clin. Chem. 59 (2013) 372e380. [116] D. Grote-Koska, S. Czajkowski, R. Klauke, E. Panten, K. Brand, G. Schumann, A candidate reference measurement procedure for cyclosporine A in whole blood, Accred Qual. Assur. 19 (2014) 147e157. [117] www.ifcc.org/ifcc-scientific-division/sd-working-groups/wg-id/(accessed 2019-07-01).