Analytical and Pharmacological Aspects of Therapeutic Drug Monitoring of mTOR Inhibitors
Maria Pieri, Nadia Miraglia, Giuliano Polichetti, Giovanni Tarantino, Antonio Acampora and Domenico Capone
Affiliation: Dipartimento di Medicina Pubblica e della Sicurezza Sociale, Universita di Napoli “Federico II”, Edificio 20, Via S. Pansini 5, I-80131, Napoli, Italy.
Mammalian Target Of Rapamycin (mTOR) inhibitors represent a new class of immunosuppressant drugs extensively used for the prevention and the treatment of graft rejection in organ transplant recipients. Their current use is due to referred low nephrotoxic effects, particularly important in kidney transplanted and/or patients with renal failure. The most representative drugs of such class are Sirolimus (Siro) and Everolimus (Rad). Both drugs show a narrow therapeutic window, therefore, monitoring of whole-blood drug levels is recommended in order to optimize the therapy. Among the available assays, Liquid Chromatography coupled with UltraViolet or Electrospray Tandem Mass Spectrometry methods (LC/UV or LC/ESI-MSMS) are the most accurate and specific ones. A reliable alternative is represented by immunoassays, which offer the opportunity to minimize sample pre-treatment, thus reducing the time between drawing blood sample and measuring the drug concentration, an important aspect in high-throughput analyses. Despite this, a limitation in the use of immunoassays for therapeutic drug monitoring is the lower specifity compared with the chromatographic methods when analysing structurally-related drugs.
New insights to optimize mTOR inhibitors regimens seem to be offered by the evaluation of CYP450 3A activity by using the probe drug approach. To such purpose, there are a number of major probe drugs used for in vivo studies including: midazolam, cortisol, lidocaine, nifedipine, dextromethorphan, erythromycin, dapsone and alfentanil.
The aim of the present paper is to report the most recent knowledge concerning this issue, supplying a critical and comprehensive review for whom are involved both in the clinical and analytical areas.
Keywords: Immunoassays, LC/UV, LC/MS, mTOR inhibitors, pharmacodynamics, pharmacokinetics, Therapeutic Drug Monitoring, Rapamycin, Everolimus, monocytes
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