| Indication |
For use after allogenic organ transplant to reduce the activity of
the patient's immune system and so the risk of organ rejection. It was
first approved by the FDA in 1994 for use in liver transplantation, this
has been extended to include kidney, heart, small bowel, pancreas,
lung, trachea, skin, cornea, and limb transplants. It has also been used
in a topical preparation in the treatment of severe atopic dermatitis. |
| Pharmacodynamics |
Tacrolimus is a macrolide antibiotic. It acts by reducing
peptidyl-prolyl isomerase activity by binding to the immunophilin
FKBP-12 (FK506 binding protein) creating a new complex. This inhibits
both T-lymphocyte signal transduction and IL-2 transcription. Although
this activity is similar to cyclosporine studies have shown that the
incidence of acute rejection is reduced by tacrolimus use over
cyclosporine. Tacrolimus has also been shown to be effective in the
topical treatment of eczema, particularly atopic eczema. It suppresses
inflammation in a similar way to steroids, but is not as powerful. An
important dermatological advantage of tacrolimus is that it can be used
directly on the face; topical steroids cannot be used on the face, as
they thin the skin dramatically there. On other parts of the body,
topical steroid are generally a better treatment. |
| Mechanism of action |
The mechanism of action of tacrolimus in atopic dermatitis is not
known. While the following have been observed, the clinical significance
of these observations in atopic dermatitis is not known. It has been
demonstrated that tacrolimus inhibits T-lymphocyte activation by first
binding to an intracellular protein, FKBP-12. A complex of
tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed
and the phosphatase activity of calcineurin is inhibited. This prevents
the dephosphorylation and translocation of nuclear factor of activated
T-cells (NF-AT), a nuclear component thought to initiate gene
transcription for the formation of lymphokines. Tacrolimus also inhibits
the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and
TNF-, all of which are involved in the early stages of T-cell
activation. Additionally, tacrolimus has been shown to inhibit the
release of pre-formed mediators from skin mast cells and basophils, and
to downregulate the expression of FceRI on Langerhans cells. |
| Absorption |
20% bioavailability; less after eating food rich in fat |
| Volume of distribution |
- 2.6±2.1 L/kg [pediatric patients]
|
| Protein binding |
75-99% |
| Metabolism |
Hepatic, extensive, primarily by CYP3A4. The major metabolite
identified in incubations with human liver microsomes is 13-demethyl
tacrolimus. In in vitro studies, a 31-demethyl metabolite has been
reported to have the same activity as tacrolimus. |
| Route of elimination |
In man, less than 1% of the dose administered is excreted
unchanged in urine. Fecal elimination accounted for 92.6±30.7%, urinary
elimination accounted for 2.3±1.1%. |
| Half life |
11.3 hours (range from 3.5 to 40.6 hours) |
| Clearance |
- 0.029 +/- 0.009 L/hr/kg [healthy subjects IV administered]
- 0.172 +/- 0.088 L/hr/kg [Healthy subjects administered PO]
- 0.138 +/- 0.071 L/hr/kg [liver transplantation pediatric patients]
- 0.038 +/-0.014 L/hr/kg [patients with renal impairment 0.02 mg/kg/4 hr, IV]
- 0.042 +/- 0.02 L/hr/kg [Mild Hepatic Impairment 0.02 mg/kg/4 hr, IV]
- 0.034 +/- 0.019 L/hr/kg [Mild Hepatic Impairment 7.7 mg PO]
- 0.017 +/- 0.013 L/hr/kg [Severe hepatic impairement 0.02 mg/kg/4 hr, IV]
|
| Toxicity |
Side effects can be severe and include blurred vision, liver and
kidney problems (it is nephrotoxic), seizures, tremors, hypertension,
hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia,
confusion. LD50=134-194 mg/kg (rat). |
