Therapeutic drug monitoring for immunosuppressants

Background: Immunosuppressants have significantly increased patient survival, e.g. in renal transplant up to 90% for the first year. Methods: Four immunosuppressants are used for clinical applications in the United States: cyclosporine (CsA) (Sandimmune and Neoral), FK 506-tacrolimus (ProGraf), mycophenolic mofetil (CellCept)-the prodrug for the mycophenolic acid (MPA), and rapamycin (RAPA) (Sirolimus). For CsA and FK 506, the rationale for monitoring is due to the variable pharmacokinetics, acute infection, dosage adjustment, non-compliance check, and for long-term maintenance therapy. Targeted whole blood concentrations ranges are: for CsA, 100-400 ng/ml depending on the methods, therapy and organs; and for FK 506, 5-20 ng/ml. For MPA, drug bioavailability-the plasma area-under-curve up to 12 h of 32.2-60.6 mg h/1 was correlated to the biopsy-proven rejection rate of < 10%. Monitoring is advocated for liver and renal transplants, for pediatrics, and for checking for non-compliance. RAPA monitoring is useful to check for variable pharmacokinetics, for non-compliance and others. The therapeutic range is tentatively targeted for 5-15 ng/ml. Monitoring methodologies are: for CsA, immunoassays such as fluorescence polarization immunoassay, and liquid chromatography (LC); for FK 506, microparticle enzyme immunoassay (MEIA); for MPA, enzyme multiplied immunoassay and LC; and for RAPA, MEIA, LC and LC-mass spectrometry. Proficiency survey programs for CsA and FK 506 are available from the US and Europe. Conclusions: Monitoring of immunosuppressants has become an essential adjunct to the drug therapy for organ transplant patients. (C) 2001 Elsevier Science B.V. All rights reserved.