Rationale for immunosuppressive drug monitoring

A prerequisite for optimizing and individualizing immunosuppressive therapy is a reliable and precise method for monitoring drug concentrations. However, not all immunosuppressive drugs require routine monitoring of blood concentrations. For instance, corticosteroids are dosed based on empirical guidelines and are not routinely monitored. Although methods have been developed to measure blood concentrations of azathioprine (14-16), this antiproliferative agent is seldom monitored by transplant centers. Blood concentrations of CsA, tacrolimus, sirolimus, and MPA are routinely monitored at transplant centers for the following reasons: (a) there is a clear relationship between drug concentration and clinical response; (b) these drugs have a narrow therapeutic index; (c) these drugs exhibit a high degree of inter- and intrapatient variability; (d) the pharmacological response can be difficult to distinguish from unwanted side effects; (e) there is a risk of poor or non-compliance because the drugs are administered for the lifetime of the graft or patient; and (f) there are significant drug-drug interactions.

The potential for drug interactions is not limited to non-immunosuppressive agents but can also occur among the various classes of immunosuppressive drugs. For instance, CsA inhibits transport of an MPA metabolite from the liver to bile resulting in lower MPA concentrations when the two drugs are used together for immunosuppressive therapy (17,18). The combination of CsA and sirolimus or tacrolimus and sirolimus results in increased blood concentrations of sirolimus (17,19). In 2004, the majority of kidney, liver, and heart transplant patients were receiving tacrolimus and MPA followed by CsA and MPA for immunosuppression, before hospital discharge (20). Tacrolimus and sirolimus or CsA and sirolimus were less commonly used, and sirolimus and mycophenolate mofetil (MMF) were the least common immunosuppressive regimens. All these drug regimens typically included corticosteroids (20). This illustrates the widespread use of combination immunosuppression and the importance of therapeutic drug monitoring, given the potential for various drug interactions.

This chapter will focus primarily on FDA-approved immunosuppressive drugs that are routinely monitored by clinical laboratories supporting solid organ transplant programs. These include CsA, tacrolimus, sirolimus, and MPA. Everolimus will be briefly discussed because it is currently in phase III clinical trials. Other drugs that are not commonly monitored, such as corticosteroids, azathioprine, and cyclophosphamide, will not be discussed further. Clinical pharmacokinetics, unwanted adverse effects, and various drug interactions will be provided for each of the chemical immunosuppressive agents. A comprehensive review of analytical methods will also be provided, along with detailed information regarding limitations and potential sources of error associated with each of the testing methodologies.

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