Home Medicine Immunosuppressant quantification in intravenous microdialysate – towards novel quasi-continuous therapeutic drug monitoring in transplanted patients
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Immunosuppressant quantification in intravenous microdialysate – towards novel quasi-continuous therapeutic drug monitoring in transplanted patients

  • Susanne Weber ORCID logo , Sara Tombelli , Ambra Giannetti , Cosimo Trono , Mark O’Connell , Ming Wen , Ana B. Descalzo , Heike Bittersohl , Andreas Bietenbeck ORCID logo , Pierre Marquet , Lutz Renders , Guillermo Orellana , Francesco Baldini and Peter B. Luppa EMAIL logo
Published/Copyright: December 15, 2020
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 59 Issue 5

Abstract

Objectives

Therapeutic drug monitoring (TDM) plays a crucial role in personalized medicine. It helps clinicians to tailor drug dosage for optimized therapy through understanding the underlying complex pharmacokinetics and pharmacodynamics. Conventional, non-continuous TDM fails to provide real-time information, which is particularly important for the initial phase of immunosuppressant therapy, e.g., with cyclosporine (CsA) and mycophenolic acid (MPA).

Methods

We analyzed the time course over 8 h of total and free of immunosuppressive drug (CsA and MPA) concentrations measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 16 kidney transplant patients. Besides repeated blood sampling, intravenous microdialysis was used for continuous sampling. Free drug concentrations were determined from ultracentrifuged EDTA-plasma (UC) and compared with the drug concentrations in the respective microdialysate (µD). µDs were additionally analyzed for free CsA using a novel immunosensor chip integrated into a fluorescence detection platform. The potential of microdialysis coupled with an optical immunosensor for the TDM of immunosuppressants was assessed.

Results

Using LC-MS/MS, the free concentrations of CsA (fCsA) and MPA (fMPA) were detectable and the time courses of total and free CsA comparable. fCsA and fMPA and area-under-the-curves (AUCs) in µDs correlated well with those determined in UCs (r≥0.79 and r≥0.88, respectively). Moreover, fCsA in µDs measured with the immunosensor correlated clearly with those determined by LC-MS/MS (r=0.82).

Conclusions

The new microdialysis-supported immunosensor allows real-time analysis of immunosuppressants and tailor-made dosing according to the AUC concept. It readily lends itself to future applications as minimally invasive and continuous near-patient TDM.

Keywords: immunosuppressants; liquid chromatography-tandem mass spectrometry (LC-MS/MS); microdialysis; optical immunosensor; point-of-care testing; therapeutic drug monitoring
Corresponding author: Peter B. Luppa, Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany, Phone: +49 89 4140 4759, E-mail:

Funding source: European Commission

Acknowledgments

We thank Christine Grubmüller and Christine Völkl for their excellent technical assistance, Francesca Salis for her help in the synthesis of CsA–O–CO2H, and Dr. Jutta Redlin for preparation of the perfusion solutions. We thank also all enrolled patients for their dedication and provision of clinical material.

  1. Research funding: This work was funded by the European Union (EU) within the project NANODEM – Nanophotonic device for multiple therapeutic drug monitoring (GA 318372) of the 7th Framework Programme. P. Marquet received research grants from Sandoz and Chiesi.

  2. Author contributions: All authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Competing interests: M. O’Connell, Chief Technical Officer and shareholder of Cornel Medical Limited. Cornel holds the IP and assets of Probe Scientific Limited, the developer of the MicroEye microdialysis device. All other authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013). The Ethics Committee of the Klinikum rechts der Isar (TUM) has approved the study (565/19 S).

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2020-1542).

Received: 2020-10-16
Accepted: 2020-12-06
Published Online: 2020-12-15
Published in Print: 2021-04-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2020-1542
Keywords for this article
immunosuppressants; liquid chromatography-tandem mass spectrometry (LC-MS/MS); microdialysis; optical immunosensor; point-of-care testing; therapeutic drug monitoring

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Home pregnancy tests: quality first
  4. Review
  5. Non-invasive determination of uric acid in human saliva in the diagnosis of serious disorders
  6. Opinion Papers
  7. Basophil counting in hematology analyzers: time to discontinue?
  8. The role of laboratory hematology between technology and professionalism: the paradigm of basophil counting
  9. Recommendations for validation testing of home pregnancy tests (HPTs) in Europe
  10. General Clinical Chemistry and Laboratory Medicine
  11. The use of preanalytical quality indicators: a Turkish preliminary survey study
  12. The Italian External Quality Assessment (EQA) program on urinary sediment by microscopy examination: a 20 years journey
  13. Non-HDL-C/TG ratio indicates significant underestimation of calculated low-density lipoprotein cholesterol (LDL-C) better than TG level: a study on the reliability of mathematical formulas used for LDL-C estimation
  14. Evaluation of the protein gap for detection of abnormal serum gammaglobulin level: an imperfect predictor
  15. Impact of routine S100B protein assay on CT scan use in children with mild traumatic brain injury
  16. Using machine learning to develop an autoverification system in a clinical biochemistry laboratory
  17. Effect of collection matrix, platelet depletion, and storage conditions on plasma extracellular vesicles and extracellular vesicle-associated miRNAs measurements
  18. Pneumatic tube transportation of urine samples
  19. Evaluation of the first immunosuppressive drug assay available on a fully automated LC-MS/MS-based clinical analyzer suggests a new era in laboratory medicine
  20. A validated LC-MS/MS method for the simultaneous quantification of the novel combination antibiotic, ceftolozane–tazobactam, in plasma (total and unbound), CSF, urine and renal replacement therapy effluent: application to pilot pharmacokinetic studies
  21. Immunosuppressant quantification in intravenous microdialysate – towards novel quasi-continuous therapeutic drug monitoring in transplanted patients
  22. Reference Values and Biological Variations
  23. Reference intervals for venous blood gas measurement in adults
  24. Cardiovascular Diseases
  25. Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy
  26. Diabetes
  27. Evaluation of the ARKRAY HA-8190V instrument for HbA1c
  28. Infectious Diseases
  29. An original multiplex method to assess five different SARS-CoV-2 antibodies
  30. Evaluation of dried blood spots as alternative sampling material for serological detection of anti-SARS-CoV-2 antibodies using established ELISAs
  31. Variability of cycle threshold values in an external quality assessment scheme for detection of the SARS-CoV-2 virus genome by RT-PCR
  32. The vasoactive peptide MR-pro-adrenomedullin in COVID-19 patients: an observational study
  33. Corrigenda
  34. Corrigendum to: Understanding and managing interferences in clinical laboratory assays: the role of laboratory professionals
  35. Corrigendum to: Age appropriate reference intervals for eight kidney function and injury markers in infants, children and adolescents
  36. Letters to the Editor
  37. A panhaemocytometric approach to COVID-19: a retrospective study on the importance of monocyte and neutrophil population data on Sysmex XN-series analysers
  38. Letter in reply to the letter to the editor of Harte JV and Mykytiv V with the title “A panhaemocytometric approach to COVID-19: a retrospective study on the importance of monocyte and neutrophil population data”
  39. SARS-CoV-2 serologic tests: do not forget the good laboratory practice
  40. Long-term kinetics of anti-SARS-CoV-2 antibodies in a cohort of 197 hospitalized and non-hospitalized COVID-19 patients
  41. Self-sampling at home using volumetric absorptive microsampling: coupling analytical evaluation to volunteers’ perception in the context of a large scale study
  42. Vortex mixing to alleviate pseudothrombocytopenia in a blood specimen with platelet satellitism and platelet clumps
  43. Comparative evaluation of the fully automated HemosIL® AcuStar ADAMTS13 activity assay vs. ELISA: possible interference by autoantibodies different from anti ADAMTS-13
  44. Significant interference on specific point-of-care glucose measurements due to high dose of intravenous vitamin C therapy in critically ill patients
  45. As time goes by, on that you can rely … preservation of urine samples for morphological analysis of erythrocytes and casts
  46. Stability of control materials for α-thalassemia immunochromatographic strip test
  47. Reformulated Architect® cyclosporine CMIA assay: improved imprecision, worse comparability between methods
  48. Urine-to-plasma contamination mimicking acute kidney injury: small drops with major consequences
  49. Automated Mindray CL-1200i chemiluminescent assays of renin and aldosterone for the diagnosis of primary aldosteronism
  50. Use of common reference intervals does not necessarily allow inter-method numerical result trending
  51. Reply to Dr Hawkins regarding comparability of results for monitoring
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