Immunosuppressant quantification in intravenous microdialysate

Immunosuppressant quantification in intravenous microdialysate – Towards novel quasi-continuous therapeutic drug monitoring in transplanted patients.

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 ( f CsA) and MPA ( f MPA) were detectable and the time courses of total and free CsA comparable. f CsA and f MPA and area-under-the-curves (AUCs) in µDs correlated well with those determined in UCs (r≥0.79 and r≥0.88, respectively). Moreover, f CsA 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.

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Authors:

Susanne Weber¹, Sara Tombelli², Ambra Giannetti², Cosimo Trono², Mark O´Connell³, Ming Wen⁴, Ana B. Descalzo⁵, Heike Bittersohl¹, Andreas Bietenbeck¹, Pierre Marquet⁶, Lutz Renders⁴, Guillermo Orellana⁵, Francesco Baldini², Peter B. Luppa¹*

¹ Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany

² Nello Carrara Institute of Applied Physics, National Research Council, 50019 Sesto Fiorentino, Italy

³ Cornel Medical Ltd., London N10 2QD, U.K.

⁴ Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany

⁵ Department of Organic Chemistry, Universidad Complutense de Madrid, 28040 Madrid, Spain

⁶ U1248 IPPRITT, INSERM, University of Limoges, CHU Limoges, 87000 Limoges, France