PROJECT OVERVIEW
NANODEM is a FP7 research project for the development of a therapeutic drug monitoring point-of-care-testing (Poct) device devoted to the measurement of immunosuppressants and related metabolites in transplanted patients.
The new tool will allow the automatic measurements of therapeutic drugs and metabolites characterized by a narrow therapeutic range and serious potential side effects.
Heart of the device will be a multi-parametric optical chip, which will make use of the recent developments in nanotechnology to convert the concentration changes of the analytes in detectable luminescent signals. Essential sections of the device will be also: the microfluidic circuit before the chip, where the dialysate is mixed with the reagents necessary for the implementation of the biological assay; the optical detection system which must be characterised by high efficiency and strong compactness; the compact hardware control unit and user interface that allow instrument control and data handling.
Clinical benefit will be an optimized dosage of the respective therapeutical drug. The patient will be connected to the device by an intravenous microdialysis catheter to allow 48-h online measurements. Based on this minimally-invasive approach, the therapeutic drugs and related metabolites will be monitored at short time intervals.
The need of mixing the dialysate with the chemical reagents and the necessity of incubation times for the bioassay implementation, unavoidable procedure for bioanalyte detection, implies that a continuous measurement of such analytes is impossible, but the miniaturisation down to micro- and nano-scales will lead to very short time intervals, of the order of a few minutes. The integration of all these sections within the Poct stand-alone device requires the convergence of competences ranging from chemistry and biochemistry to optics and medicine as well as the convergence of micro and nanotechnologies, such as micro/nanofluidics, microdialysis and micro/nanosensing.
Concept
The continuous measurement of therapeutic drugs and metabolites is a strong requirement coming from physicians in transplantation surgery, pulmonary and critical care medicine, psychiatry.
Drugs of interest are therapeutics with a narrow therapeutic window, which regularly pose considerable problems in initial and ongoing dosing. These drugs are often subject to polymorphic metabolism with considerable inter- and intra-individual variability requiring therapeutic drug monitoring (TDM). TDM, however, is regularly performed with one blood sample per dosing interval only due to practical problems, with the measurement of the trough value, i.e. the plasma level of a pharmaceutical product measured just before the next dose. In the last couple of years it has become increasingly evident that improved patient outcome results from pharmacokinetic dosing strategies requiring multiple sampling with the modelling of time-concentration curves. Strategies based on sparse sampling have been developed for clinical purposes estimating the area under the concentration time curve (AUC) and have been shown to substantially improve patient outcome. Further substantial progress can be expected from continuous measurement rather than estimation of the AUC.
Examples of interesting drugs in this regard are immunosuppressants. Of particular interest are the calcineurin inhibitors cyclosporin A and tacrolimus (FK 506) and the inhibitors of the mammalian mTOR proteins, rapamycin (sirolimus) and everolimus as well as mycophenolic acid (which inhibits an enzyme needed for the growth of T- and B-cells). These pharmaceuticals are clinically used as immunosuppressants after organ transplantation and require life-long monitoring because of their narrow therapeutic window, in order to optimize efficacy avoiding as much as possible adverse events. They are accumulated in blood cells (erythrocytes, leucocytes, lymphocytes). Plasma concentrations of these drugs are somewhat correlated to the intracellular concentrations in a temperature-dependent manner and might also be accessible for analysis in case of intravenous samples. The analytical sensitivity, however, has to be very high. Also some metabolites have been shown to be of clinical interest with respect to therapeutic efficiency and may be helpful for therapeutic decisions. Moreover, it is generally admitted that the free fraction (the amount of drug not bound to proteins) is responsible for the pharmacological activity but also for the side effects. For immunosuppressive drugs, the free fraction ranges between 2-8%. With these features in mind, nanotech-based optical biosensors can fulfil this requirement thanks to their capability to achieve high sensitivities and very low limit of detections, unreachable with conventional sensors. Since multiple combinations of these immunosuppressant drugs are common in clinical therapy, multiple sensing is a prerequisite for POC-testing of these analytes.
Project objective
The aim of the project is the development of a novel TDM point-of-care-testing (POCT) device for the automatic measurement of immunosuppressants and related metabolites in transplanted patients characterized by a narrow therapeutic range and serious potential side effects.
The patient will be connected to the POCT device by an intravenous microdialysis catheter to allow 48 hour online measurements. The data will be used to calculate the individual pharmacokinetics of the drug of interest by applying the AUC concept. Clinical benefit will be an optimized dosage of the respective therapeutical drug.
The new tool will allow the automatic measurements of therapeutic drugs and metabolites characterized by a narrow therapeutic range and serious potential side effects.
Heart of the device will be a multi-parametric optical chip, which will make use of the recent developments in nanotechnology to convert the concentration changes of the analytes in detectable luminescent signals. Essential sections of the device will be also: the microfluidic circuit before the chip, where the dialysate is mixed with the reagents necessary for the implementation of the biological assay; the optical detection system which must be characterised by high efficiency and strong compactness; the compact hardware control unit and user interface that allow instrument control and data handling.
Clinical benefit will be an optimized dosage of the respective therapeutical drug. The patient will be connected to the device by an intravenous microdialysis catheter to allow 48-h online measurements. Based on this minimally-invasive approach, the therapeutic drugs and related metabolites will be monitored at short time intervals.
The need of mixing the dialysate with the chemical reagents and the necessity of incubation times for the bioassay implementation, unavoidable procedure for bioanalyte detection, implies that a continuous measurement of such analytes is impossible, but the miniaturisation down to micro- and nano-scales will lead to very short time intervals, of the order of a few minutes. The integration of all these sections within the Poct stand-alone device requires the convergence of competences ranging from chemistry and biochemistry to optics and medicine as well as the convergence of micro and nanotechnologies, such as micro/nanofluidics, microdialysis and micro/nanosensing.
Concept
The continuous measurement of therapeutic drugs and metabolites is a strong requirement coming from physicians in transplantation surgery, pulmonary and critical care medicine, psychiatry.
Drugs of interest are therapeutics with a narrow therapeutic window, which regularly pose considerable problems in initial and ongoing dosing. These drugs are often subject to polymorphic metabolism with considerable inter- and intra-individual variability requiring therapeutic drug monitoring (TDM). TDM, however, is regularly performed with one blood sample per dosing interval only due to practical problems, with the measurement of the trough value, i.e. the plasma level of a pharmaceutical product measured just before the next dose. In the last couple of years it has become increasingly evident that improved patient outcome results from pharmacokinetic dosing strategies requiring multiple sampling with the modelling of time-concentration curves. Strategies based on sparse sampling have been developed for clinical purposes estimating the area under the concentration time curve (AUC) and have been shown to substantially improve patient outcome. Further substantial progress can be expected from continuous measurement rather than estimation of the AUC.
Examples of interesting drugs in this regard are immunosuppressants. Of particular interest are the calcineurin inhibitors cyclosporin A and tacrolimus (FK 506) and the inhibitors of the mammalian mTOR proteins, rapamycin (sirolimus) and everolimus as well as mycophenolic acid (which inhibits an enzyme needed for the growth of T- and B-cells). These pharmaceuticals are clinically used as immunosuppressants after organ transplantation and require life-long monitoring because of their narrow therapeutic window, in order to optimize efficacy avoiding as much as possible adverse events. They are accumulated in blood cells (erythrocytes, leucocytes, lymphocytes). Plasma concentrations of these drugs are somewhat correlated to the intracellular concentrations in a temperature-dependent manner and might also be accessible for analysis in case of intravenous samples. The analytical sensitivity, however, has to be very high. Also some metabolites have been shown to be of clinical interest with respect to therapeutic efficiency and may be helpful for therapeutic decisions. Moreover, it is generally admitted that the free fraction (the amount of drug not bound to proteins) is responsible for the pharmacological activity but also for the side effects. For immunosuppressive drugs, the free fraction ranges between 2-8%. With these features in mind, nanotech-based optical biosensors can fulfil this requirement thanks to their capability to achieve high sensitivities and very low limit of detections, unreachable with conventional sensors. Since multiple combinations of these immunosuppressant drugs are common in clinical therapy, multiple sensing is a prerequisite for POC-testing of these analytes.
Project objective
The aim of the project is the development of a novel TDM point-of-care-testing (POCT) device for the automatic measurement of immunosuppressants and related metabolites in transplanted patients characterized by a narrow therapeutic range and serious potential side effects.
The patient will be connected to the POCT device by an intravenous microdialysis catheter to allow 48 hour online measurements. The data will be used to calculate the individual pharmacokinetics of the drug of interest by applying the AUC concept. Clinical benefit will be an optimized dosage of the respective therapeutical drug.
Figure 1
Figure 1 shows a block diagram of the proposed POCT device. In the proposed device, the biological sample drawn from blood by means of microdialysis will flow through a microfluidic section where the dialysate will be mixed with the reagents necessary to perform the bioassay and will be then pumped through a nanostructured chip where the determination of the different analytes will take place. A compact optoelectronic system will be developed for the control, acquisition and processing of the optical signals. A user interface optimized for the end-user needs will allow an easy instrument handling with respect to instrument operation, data storage, display of results and device calibration. All the different parts will be integrated in a stand-alone device to be applied to the patient.
The development of the POCT device will originate from the needs defined by health care professionals and will be guided according to the evidence-based medicine criteria and best clinical practice guidelines.
Automatic measurement at short time intervals of the immunosuppressants and related metabolites will offer new possibilities to physicians in keeping under control the complete recovery of patients and/or the efficiency of the administrated therapies.