Tacrolimus

Tacrolimus is an immunosuppressive macrolide agent obtained by fermentation of Streptomyces tsukubaensis, found in Japan . Tacrolimus has been studied in transplant patients of heart , lung , liver , kidney , pancreas , small intestine and bone marrow , being very effective in the prevention of rejection resistant to corticosteroids and cyclosporine. In this sense, tacrolimus is 10 to 100 times more potent than cyclosporine. Topically, tacrolimus is used for the treatment of adult and child atopic dermatitis .

Summary

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  • 1 Mechanism of action
  • 2 Determination of levels
  • 3 Contraindications
  • 4 interactions
  • 5 Sources

Mechanism of action

Tacrolimus induces immunosuppression by inhibiting the first phase of T-cell activation. In this first phase, transcription of certain factors such as interleukin (IL) -2, IL-3, IL-4, the stimulating factor, is activated. of granulocyte-macrophage colonies and interferon gamma, factors that allow T cells to progress from the G0 to G1 phase. Tacrolimus binds to an immunophylline, FKBPB12, forming a complex that inhibits the phosphatase activity of calcineurin. Because calcineurin catalyzes a dephosphorylation reaction critical for lymphokine gene transcription, inhibition of calcineurin results in blocking the transduction of a nuclear factor necessary for activation of B and T cells. of T cell activators,

In atopic dermatitis, tacrolimus works by inhibiting inflammation by reducing T cell activity. Tacrolimus also binds to steroid receptors on the cell surface, inhibiting the release of mediators from mast cells, regulating the number of IL-8 receptors, decreasing intracellular adhesion and E-selectin expression in blood vessels. All these actions result in a decrease in the recognition of antigens and in a regulation of the inflammatory cascade. Topical tacrolimus does not inhibit collagen synthesis and does not cause atrophy of the skin as occurs in the case of corticosteroids.

Determination of levels

There are several immunoassay techniques available to determine the concentration of tacrolimus in the blood, including a semi-automated microparticle enzyme immunoassay (MEIA). The comparison of the concentrations indicated in the published literature and the individual values ​​determined in clinical practice should be carefully evaluated, taking into account the analysis methods used. In current clinical practice, whole blood levels are determined by immunoassay methods.

Minimum blood levels of tacrolimus should be monitored during the start of the post-transplant period. When administered orally, trough levels in the blood should be analyzed approximately 12 hours after the dose, just before the next administration. The frequency of blood level control should be based on clinical needs. Prograf is a slow-clearance medication, so it may take several days for dose adjustments to be reflected in blood levels. Valley blood levels should be determined approximately twice a week during the immediate post-transplant period and then periodically during maintenance therapy. Valley levels of tacrolimus in blood should also be monitored after dose adjustments,

Analysis of clinical studies indicates that the majority of patients can be successfully controlled if blood trough levels of tacrolimus remain below 20 ng / ml. The patient’s clinical status needs to be taken into account when interpreting blood levels .

Dose adjustments in specific patient populations, all indications:

Patients with hepatic impairment: In patients with severe hepatic impairment, a dose reduction may be necessary to maintain minimum blood levels within the recommended limits.

Patients with renal impairment: renal function does not affect the pharmacokinetics of tacrolimus, therefore dose adjustments are generally not necessary. However, due to the nephrotoxic potential of tacrolimus, careful monitoring of renal function is recommended, with serial determinations of serum creatinine concentration, calculation of creatinine clearance, and monitoring of urine output.

Contraindications

Systemic tacrolimus should only be used by physicians experienced in immunosuppressive therapy associated with organ transplants. Immunosuppression increases patients’ susceptibility to infections, and neoplastic diseases, especially lymphomas, can develop. Patients treated with tacrolimus topically who develop lymphadenopathy should be investigated, due to the potential risk of developing lymphomas or other lymphoproliferative disorders. In cases of lymphadenopathy or acute infectious mononucleosis, discontinuation of treatment with topical tacrolimus should be considered.

Patients treated with systemic tacrolimus should be managed in adequate facilities prepared for immunosuppressed patients. During immunosuppressive therapy, potentially fatal viral, bacterial, fungal, and protozoal infections can develop. Similarly, administration of tacrolimus can activate latent viral infections, especially herpes virus.

The use of topical tacrolimus is associated with an increased risk of infection with the chickenpox or herpes simplex virus. In the presence of these infections, the benefit of tacrolimus therapy should be evaluated against the possible risks. Patients should be warned to report any signs of infection immediately to their physician.

Systemic treatment with tacrolimus is associated with significant nephrotoxicity, such that patients with pre-existing kidney disease or kidney failure must be carefully monitored. In kidney transplant patients, treatment with tacrolimus should be delayed 48 hours or more in cases where oliguria or kidney failure occurs. Other nephrotoxic drugs, especially cyclosporine, should be avoided and blood levels of tacrolimus should be frequently measured.

Patients with liver disease and those treated with other drugs that may affect tacrolimus metabolism may be susceptible to a greater toxic effect of tacrolimus. The use of tacrolimus in liver transplant patients showing liver failure additionally leads to a risk of renal toxicity due to increased blood levels of the immunosuppressant.

Systemic tacrolimus should be used with caution in patients with pre-existing hypertension. Treatment with tacrolimus has been associated with moderate hypertension, but cases of severe hypertension have also been described. Antihypertensive treatment may be necessary, but potassium-sparing diuretics should be avoided since tacrolimus can cause hypokalemia. Furthermore, calcium antagonists should be used with caution as some of them interfere with the metabolism of tacrolimus.

Systemic tacrolimus should be used with caution in patients with established heart disease. Cardiac hypertrophies associated with the use of tacrolimus have been reported in children and adults, although these appear to be reversible when doses are reduced or treatment is discontinued.

High blood levels of tacrolimus are associated with neurotoxicity, including the development of seizures, especially in patients with kidney or liver failure. Tacrolimus levels should be carefully monitored in patients with some type of epileptic disease.

Interactions

Tacrolimus is metabolized via hepatic cytochrome P-450 (CYP) 3A4. Drugs that inhibit this isoenzyme can reduce metabolism by increasing blood levels of tacrolimus and therefore the risk of toxicity. Some of these agents are: amiodarone, inhibitors of anti-retroviral, bromocriptine, cimetidine, clarithromycin, dalfopristin, quinupristin, danazol, delavirdine, fluoxetine, fluvoxamine, metronidazole, methylprednisolone, mifepristone, RU-486, quinidine, quinine, protease and troleandomycin .

Drugs such as carbamazepine, phosphenytoin, nevirapine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, and troglitazone, which induce cytochrome P-450 3A4 may increase blood levels of tacrolimus. Monitoring of blood levels of tacrolimus is recommended if any of these agents is used at the same time.

Concomitant administration of erythromycin and tacrolimus may increase the levels of the latter, increasing the risk of nephotoxicity. The use of this antibiotic should be avoided and if necessary, tacrolimus levels should be monitored.

Renal failure, delirium, and high concentrations of tacrolimus have been reported in patients simultaneously treated with tacrolimus and nefazodone.

Some calcium antagonists (eg diltiazem, nicardipine, nifedipine, and verapamil) and tacrolimus may show interactions since they are all metabolized by cytochrome P450 3A4.

The concomitant use of nephrotoxic agents should be considered with caution to avoid additive effects. Some agents that can cause nephrotoxicity are aminoglycoside antibiotics, amphotericin B, cisplatin, foscarnet, ganciclovir, bacitracin or polymyxin B, and vancomycin. Acetaminophen, aspirin, and NSAIDs should be used with caution as they can mask fever, pain and inflammation, and other symptoms of infection.

Concomitant administration of tacrolimus and cyclosporine increases the risk of nephrotoxicity due to additive or synergistic effects. It is recommended not to use both drugs simultaneously. When switching from cyclosporine to tacrolimus, it is recommended to wait at least 24 h after the last dose of cyclosporine before starting treatment with tacrolimus.

Additive effects can also be seen with other antineoplastic and immunosuppressive drugs. Patients can develop superimmunosuppression with an increased risk of infections, leukemia, lymphomas, and myelodysplastic and lymphoproliferative syndromes.

The immune response of immunocompromised patients to vaccines is reduced and higher doses of these are needed, as well as a higher frequency of revaccination. Live virus vaccines are contraindicated during treatment with immunosuppressive drugs because virus replication and adverse reactions are enhanced. For the same reason, patients treated with tacrolimus should not be exposed to other people who have recently been vaccinated with live virus vaccines. Less frequently, killed virus vaccines are associated with a higher incidence of side effects in immunocompromised patients.

 

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