++
Tacrolimus (also known as FK506) is a macrolide compound with
immunosuppressant actions that is used for the prevention of graft
rejection in solid organ transplant patients.1,2 Currently,
it is approved for use in heart, liver, and renal transplant patients.1 It
is also used in 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 result from its ability to block the production
of intraleukin-2 and other cytokines produced by T-lymphocytes.3 Tacrolimus
binds to FK-binding protein (FKPB), 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.
++
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 two 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 Two different assay systems
are in widespread use. The enzyme-linked immunosorbent assay (ELISA;
Pro-Trac, IncStar) and microparticulate enzyme immunoassay (MEIA;
IMx, Abbott Diagnostics) incorporate the same monoclonal antibody.
Using blood as the assay matrix, these two different assay systems
produce similar results.6–8 For the purposes of
the pharmacokinetic computations and problems presented in this
book, tacrolimus concentrations in the blood determined with the
ELISA or MEIA assay systems will be used. Because predose trough
steady-state concentrations correlate well with steady-state area
under the concentration/time curve measurements, tacrolimus
trough concentrations are used in patient monitoring situations.5,9,10
++
Desired tacrolimus concentrations differ between the various
types of organ transplants, change with time during the post transplantation
phase, and are determined by protocols specific to the transplantation
service and institution.1,2,5 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 from 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.1,5 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 rejected kidney transplant,
it is possible to remove the graft and ...