Tacrolimus (also known as FK506) is a macrolide-based calcineurin inhibitor, with immunosuppressant actions, that is used for the prevention of graft rejection in solid organ transplant patients.1 Currently, it is approved for use in heart, liver, and renal transplant patients. It is also used in lung, heart-lung, and other solid organ transplant recipients, as well as the treatment of graft-versus-host disease in hematopoietic stem cell transplant patients.1,2 The immunomodulating effects of tacrolimus are due to its ability to block the production of interleukin-2 and other cytokines produced by T lymphocytes.1,2, and 3 Tacrolimus binds to FK-binding protein-12 (FKPB-12), an intracellular cytoplasmic protein found in T cells. The tacrolimus-FKPB complex interacts with calcineurin, inhibits the catalytic activity of calcineurin, and blocks the production of intermediaries involved with the expression of genes regulating the production of cytokines.
THERAPEUTIC AND TOXIC CONCENTRATIONS
The therapeutic range for tacrolimus used by most transplantation centers is 5-20 ng/mL in blood.1,4,5 Although, plasma tacrolimus concentrations have been measured and an equivalent therapeutic range in this matrix suggested (0.5-2 ng/mL), the most widely used assays for the drug use blood samples.4,5 Because tacrolimus is extensively bound to erythrocytes, blood concentrations average about 15 times greater than concurrently measured serum or plasma concentrations.5 Using blood as the assay matrix, specific immuno-assay systems are in widespread use.6,7, and 8 For the purposes of the pharmacokinetic computations and problems presented in this book, tacrolimus concentrations in the blood determined with these specific immunoassay systems or high-pressure liquid chromatography (HPLC) will be used. Because predose trough steady-state concentrations correlate well with steady-state area under the concentration/time curve (AUC) measurements, tacrolimus trough concentrations are used in patient-monitoring situations.5,9,10
Desired tacrolimus concentrations differ between the various types of transplants, change with time during the posttransplantation phase, and are determined by protocols specific to the transplantation service and institution.1,2,11,12,13,14, and 15 Because of these factors, it is very important for clinicians to be aware of these situations since acceptable tacrolimus concentrations under these different circumstances may be different than those given by the clinical laboratory or those suggested in this textbook.
For patients receiving solid organ transplants such as kidney, liver, heart, lung, or heart-lung transplantation, the goal of tacrolimus therapy is to prevent acute or chronic rejection of the transplanted organ while minimizing drug side effects.1,12,13,14, and 15 In this case, the recipient’s immune system detects foreign antigens on the donor organ which produces an immunologic response against the graft. This leads to inflammatory and cytotoxic effects directed against the transplanted tissue, and produces the risk of organ tissue damage and failure. In the case of a ...