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