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).
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.
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).
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.
Funding source: European Commission
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.
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.
Author contributions: All authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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.
Informed consent: Informed consent was obtained from all individuals included in this study.
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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The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2020-1542).
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