Susanne Weber, Sara Tombelli, Ambra Giannetti, Cosimo Trono, Mark O’Connell, Ming Wen, Ana B. Descalzo, Heike Bittersohl, Andreas Bietenbeck, Pierre Marquet, Lutz Renders, Guillermo Orellana, Francesco Baldini, Peter B. Luppa
December 15, 2020
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.