Therapeutic drug monitoring of novel immunosuppressants

Cattaneo, Dario (2006). Therapeutic drug monitoring of novel immunosuppressants. PhD thesis The Open University.



Therapeutic drug monitoring is primarily undertaken for narrow therapeutic index drugs, such as immunosuppressants. These drugs have reduced the incidence of acute rejection and improved allograft survival. However, due to their narrow therapeutic index, small variations in blood levels may result in inadequate levels of immunosuppression or toxic drug concentrations. To overcome these problems individual dose regimen based-on pharmacokinetic monitoring has been proposed in the past years. Indeed, several studies have previously documented a significant association between cyclosporine whole blood levels and patient's clinical outcome, expressed as rejection episodes as well as drug-related adverse events.

Novel immunosuppressive agents have been recently introduced on the market (such as rapamycins and mycophenolic acid-releasing formulations). However, data on their pharmacokinetics, which in turn could be useful for the definition of therapeutic ranges, are scanty. To address this issue we have used a chromatographic method for the measurement of mycophenolic acid levels in kidney transplant recipients. Although this immunosuppressant is usually given in a fixed daily dose regimen, we found a positive correlation between drug levels, but not dose, and renal function. As additional analysis, significant pharmacokinetic interactions between mycophenolic acid and concomitant immunosuppressive regimens have been identified. Similarly, novel chromatographic methods for the analysis of rapamycins in the whole blood have been developed in our laboratory, and applied to identify pharmacokinetic interactions between these and other immunosuppressive agents. In the last part of my research project, I have also presented preliminary data on the application of pharmacogenetics analysis in patients given cyclosporine as part of their immunosuppressive regimen.

In conclusion, it can be reasonably speculated that TDM based on pharmacokinetic, as well as novel pharmacogenetic approaches, can be considered as reliable tools to guide drug dosing in organ transplantation setting, ultimately resulting in a significant improvement of long term graft and patient survival.

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