The Importance of Therapeutic Drug Monitoring by LC/MS Through the Lens of Organ Transplantation

By June 29, 2017


Improving patient outcomes by advancing TDM with LC-MS

In our previous therapeutic drug monitoring post, we mapped the trends that are fueling a surge of clinical interest in TDM Asia. These include improved cultural acceptance and availability of organ transplantation, better understanding of the benefits of precision medicine for patients, and the availability of accurate and specific quantitative tests on LC/MS and immunoassay platforms.

Today let’s look at the area of organ transplantation once again as an example of how the TDM field is developing.

Powerful immunosuppressant drugs are prescribed to recipients of organ transplants to lower the possibility of graft rejection occurring.

Introduction of powerful drugs such as cyclosporin, everolimus, sirolimus, tacrolimus, and mycophenolic acid since the 1990s has resulted in vastly increased survival rates post-transplantation. Setting the correct dosage regime, however, is complicated due to the narrow therapeutic window of the drugs in question. The need for precise and accurate quantitation of immunosuppressant drugs in an individual’s serum is clear.

From immunoassays…

Initially, almost all laboratories turned to immunoassay platforms. While they offered benefits such as automation and rapid turnaround time (TAT), immunoassay platforms have also proven to have drawbacks in some cases. Immunoassays can be non-specific and may cross-react with drug metabolites, leading to over-estimation of the parent drug. This can lead to a patient being under-dosed and facing an increased risk of graft rejection.

Since the 2000s this problem[1] of cross-reactivity in immunoassays for cyclosporine and metabolites has been well known and characterized. The importance of specificity is especially clear when one considers that trough levels of AM1, the major metabolite of cyclosporine, can be equivalent to or even exceed that of the parent drug level.

A similar limitation to a lesser extent has been observed for tacrolimus, sirolimus, and everolimus. Immunoassay manufacturers have worked to improve the specificity of their immunoassays, but issues with cross-reactivity have still been observed[2].

In view of these challenges, we started to see more governments, clinical labs and universities collaborating to advance the development TDM in Asia to improve patient outcomes over the years.

… To LC-MS assays

South Korea is in the advance guard when it comes to TDM by LC-MS. Korea, which has a well-developed medical system supported by a national health insurance system, started using LC-MS in clinical labs for immunosuppressant TDM more than 10 years ago. In 2013, Soon Chun Hyang University’s Bucheon Hospital published a study comparing a UPLC-MS approach with chemiluminescence immunoassay (CLIA) in the determination of cyclosporin A and tacrolimus levels in whole blood.

In an analysis of over 3,400 patient samples the majority of blood samples indicated levels of cyclosporin A and tacrolimus that were systematically higher when measured by CLIA than by UPLC-MS. Again, this is thought to be at least partly due to significant metabolite or structural analogue cross-reactivity, which can result in overestimation of drug concentration

Concentrations measured by UPLC-MS were observed to be approximately 18% lower than those measured by CLIA for cyclosporin A.

As shown in South Korea’s clinical breakthrough in TDM by LC/MS, we see an ample market potential and acute need for leveraging cutting-edge LC/MS in advancing TDM’s development in Asia.

IATDMCT meeting

The upcoming IATDMCT meeting being held in Kyoto Japan is just around the corner in September.  At the industry workshop, Waters expert will look into the future and new TDM applications for anit-cancer drugs and the challenges to be addressed and overcome when analyzing monoclonal antibodies.

In addition, Dr. CS Ho, Adjunct Assistant Professor at the Chinese University of Hong Kong, the highly regarded clinical LC/MS pioneer in Asia will speak about LC/MS versus Immunoassay for Immunosuppressant TDM at an invitation only evening seminar and dinner event.

Come visit our booth in Kyoto at IATDMCT from September 24th to 27th to learn more the latest TDM trends and analysis methods in Asia.

 

References:

[1]

  • Stenton SB, Partovi N, Ensom MH. Sirolimus: the evidence for clinical pharmacokinetic monitoring. Clin Pharmacokinet 2005; 44: 769–786. Google Scholar
  • Wallemacq PE, Lee SC, Lhoest G. Cross-reactivity of cyclosporine metabolites in two different radioimmunoassays in which the same specific monoclonal antibody is used. Clin Chem 1990; 36: 385. Google Scholar
  • Lensmeyer GL, Wiebe DA, Carlson IH,. Three commercial polyclonal immunoassays for cyclosporine in whole blood compared: 2. Cross-reactivity of the antisera with cyclosporine metabolites. Clin Chem 1990; 36: 119–123. Google Scholar
  • Yatscoff RW, Rosano TG, Bowers LD. The clinical significance of cyclosporine metabolities. Clin Biochem 1991; 24: 23–35. Google Scholar
  • Bleck JS, Schlitt HJ, Christians U,. Ciclosporin metabolite pattern in blood and urine of kidney graft patients in relation to liver function. Eur J Clin Pharmacol 1991; 40: 565–569. Google Scholar Medline

[2] Wallemacq P, Goffinet JS, O’Morchoe S, . Multi-site analytical evaluation of the Abbott ARCHITECT tacrolimus assay. Ther Drug Monit 2009; 31: 198–204. Google Scholar

 

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