Tacrolimus (Dosage)

Tacrolimus is an immunosuppressive drug used mainly after allogeneic transplantation to reduce the activity of the immune system and thus reduce the risk of rejection. There is great variability in the doses of the drug required. One of the main determinants of these differences are some polymorphisms in the CYP3A5 and CYP3A4 genes, the main cytochromes involved in its metabolism.

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressant drug used mainly after allogeneic transplants to reduce the activity of the immune system and thus decrease the risk of rejection.

ACTION MECHANISM

Immunosuppressant drug from the group of calcineurin inhibitors. Its mechanism of action is based on the inhibition of the activation of T-lymphocytes by binding to the intracellular protein FKBP12, forming a complex that competitively inhibits calcineurin. Tacrolimus thus inhibits the formation of cytotoxic lymphocytes, which are the main responsible for the rejection of the implant. It inhibits the activation of T cells and the proliferation of B lymphocytes dependent on helper T cells, as well as the formation of lymphokines by preventing the transcription of a specific group of lymphokine genes (such as interleukins 2, 3 and interferon-γ and preventing the expression of the interleukin-2 receptor).

CONTRAINDICATIONS

Tacrolimus is contraindicated in patients with known hypersensitivity to tacrolimus, to other macrolides or to any of its excipients (risk of anaphylaxis with intravenous administration due to its content of hydrogenated and polyoxyethylenated castor oil). It can contain lactose and therefore avoid if there exist hereditary intolerance to galactose or glucosa/ galactose malabsorption.

CAUTIONS

During the initial post-transplant period, controls must be performed: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolyte levels (particularly potassium), liver and kidney function tests, hematological parameters , coagulation values and plasma protein determination. In case of clinically significant variations, consider dose adjustment of the immunosuppressant.

Additional monitoring of tacrolimus concentrations during episodes of diarrhea should be carried out.

Tacrolimus is a slow clearance medication: it may take several days before adjustments in the dose are reflected in blood levels.

Risk of ventricular hypertrophy or hypertrophy of the septum mainly in children with blood tacrolimus concentrations higher than the recommended maximum levels. The risk of suffering these clinical conditions in increased in cases of previous cardiac pathology, use of corticosteroids, hypertension, renal or hepatic dysfunction, infections, fluid overload and edema. High risk patients should be monitored, using ECG, before and after transplantation and in case of alterations, dose reduction or change of immunosuppressive agent should be evaluated.

Use of tacrolimus increases the risk of opportunistic infections and the possible development of lymphoproliferative disorders associated with Epstein Barr virus infection, especially in very small children (less than 2 years old), which are seronegative for EBV-VCA.

Due to the risk of suffering from malignant changes in the skin, exposure to sunlight and UV rays during treatment should be reduced.

SIDE EFFECTS

Cardiac disorders: ischemic alterations of the coronary arteries, tachycardia.

Blood and lymphatic system disorders: anemia, leukopenia, thrombocytopenia, leukocytosis, abnormal red cell analysis.

Nervous system disorders: tremor, headache, convulsions, alterations of consciousness, paresthesias and dysesthesias, peripheral neuropathies, dizziness, difficulty in writing.

Eye disorders: blurred vision, photophobia, ocular alterations.

Ear and labyrinth disorders: tinnitus.

Respiratory, thoracic and mediastinal disorders: dyspnea, pulmonary parenchyma alterations, pleural effusion, pharyngitis, colds, nasal congestion and inflammations.

Gastrointestinal disorders: diarrhea, nausea, gastrointestinal inflammatory disorders, perforation and gastrointestinal ulcers, gastrointestinal hemorrhages, stomatitis and ulcers, ascites, vomiting, gastrointestinal and abdominal pain, constipation, gastrointestinal signs and symptoms

Renal and urinary disorders: renal failure, oliguria, renal tubular necrosis, toxic nephropathy.

Disorders of the skin and subcutaneous tissue: itching, rash, alopecia, acne, increased sweating, burning and itching.

PHARAMACOLOGIC INTERACTIONS

  • Antacids: do not administer within 2 hours before or after taking tacrolimus.
  • Ciclosporin can potentially inhibit CYP3A4-mediated metabolism of tacrolimus: The half-life of cyclosporin is extended when it is administered simultaneously with tacrolimus and additive/synergistic nephrotoxic effects can occur. The combination of ciclosporin and tacrolimus is not recommended, and caution should be exercised when administering tacrolimus to patients previously treated with ciclosporin.
  • Tacrolimus can interact with antifungals (such as ketoconazole, fluconazole, itraconazole, and voriconazole), the macrolide antibiotic erythromycin, or HIV protease inhibitors.
  • Potential inhibitors of tacrolimus metabolism are: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.
  • Avoid high potassium intake or potassium-sparing diuretics.
  • Vaccines may be less effective during treatment with tacrolimus. The use of live attenuated vaccines while taking tacrolimus should be avoided.

BRAND NAMES

  • Advagraf ®
  • Modigraf ®
  • Prograf ®
  • Tacni ®
  • Tartrime ®

Genes analyzed

CYP3A5

Bibliography

Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24.

Deininger KM, Anderson HD, Patrinos GP, et al. Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data. Pharmacogenomics J. 2024 May 15;24(3):14.

Rojas L, Neumann I, Herrero MJ, et al.Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 2015 Feb;15(1):38-48.

Tang HL, Xie HG, Yao Y, et al. Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressors than expressors. Pharmacogenet Genomics. 2011 Nov;21(11):713-20.

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