Immunosuppressive Agents

Immunosuppressive agents are used to prevent rejection of transplanted organs. Solid organ transplant recipients usually receive at least three antirejection agents, making it difficult to determine the contribution of a particular agent. The endpoint for evaluating these agents is occurrence of organ rejection. In many cases, the symptoms of rejection are similar to adverse effects of some of the drugs patients receive. Thus, it is often necessary to confirm acute rejection with a biopsy. The factors listed above complicate the evaluation of exposure-response relationships for immunosuppressive agents. However, because the transplant community appreciates the importance of exposure-response relationships for the safety and efficacy of immunosuppressive agents, studies of these relationships are common.

Van Gelder, et al. [45] evaluated the relationship between exposure and response for kidney transplant recipients receiving mycophenolate mofetil (MMF). Mycophenolate mofetil is a prodrug for the active moiety mycophenolic acid (MPA). The investigators randomized 154 adult recipients of kidney transplants to receive MMF treatment targeted at three predefined MPA AUC values (16.1, 32.2, and 60.6 pg*hr/mL). During the first six months after transplantation, investigators collected plasma samples for nine AUC evaluations. The primary endpoint of this six-month study was occurrence of biopsy-proven rejection. The analysis indicated that MPA predose concentration and MPA AUC are significantly related to the incidence of biopsy-proven rejection, and MMF dose is significantly related to the incidence of adverse events.

Although the study described above indicates it is possible to determine an exposure-response relationship for immunosuppressive agents, using the information to select a dose for patients is not simple. Most of the oral immunosuppressive agents have high inter- or intrapatient pharmacokinetic variability. Also, because the transplanted organ may participate in elimination of the drug, the pharmacokinetics of the drug may vary based on the time post transplantation. The exposure-response relationship may vary depending on doses of the other immunosuppressive agents in the regimen. For these reasons, transplant centers use therapeutic drug monitoring for some agents, including cyclosporine and tacrolimus. However, there is still debate regarding the appropriate exposure measure for therapeutic drug monitoring—minimum plasma concentration, full AUC, or limited sampling AUC.

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