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Tacrolimus

Up Cyclosporin Tacrolimus


Immunosuppressant

Mode of action

  • Calcineurin inhibitor
    • results in inhibition of the signal transduction pathway leading to to T-cell activation
    • although cyclosporin also inhibits calcineurin (via a different mechanism), tacrolimus is 10-100 times more effective as an immunosuppressant

Pharmacokinetics

  • Adminstration: enteral or IV
    • rapid but incomplete absorption
    • bioavailability ~25%. Lower in Afro-Caribbeans and Hispanics. 
    • speed and extent of absorption decreased by presence of food
  • Distribution
    • extensively bound to erythrocytes
    • plasma protein binding as high as 99%, predominantly to alpha1-acid glycoprotein and albumin
    • wide distribution into most tissues. Crosses placenta and is present in breast milk at similar concentrations to plasma
  • Elimination
    • almost completely metabolized via cytochrome P450 in the liver and to lesser extent in intestinal mucosa and then excreted in bile
    • at least one metabolite has immunosuppressant effects but main immunosuppressive activity is from parent drug
    • elimination half life 12-19 hours
    • clearance higher in children, reduced in patients with severe hepatic dysfunction (Child Pugh score >10)

Clinical indications

  • solid organ and bone marrow transplants
    • primary immunosuppression
    • rescue therapy for rejection
    • as effective or more effective than cyclosporin for:
      • renal transplants
      • liver transplants
      • heart transplants
      • lung transplants
      • simultaneous pancreas and renal transplants
      • bone marrow transplants

Adverse effects

  • nephrotoxic
  • neurotoxic
  • diarrhoea and other GI disturbance
  • increased risk of infections and malignancy
  • hypertension
  • diabetes mellitus
  • hypercholesterolaemia

Drug interactions

Potentiated by cytochrome P450 inhibitors:

  • calcium antagonists
  • imidazole anti-fungals (eg fluconazole, itraconazole)
  • macrolides (eg clarithromycin, erythromycin)
  • prokinetics (eg metoclopramide, cisapride)
  • bromocriptine
  • cimetidine
  • corticosteroids
  • cyclosporin
  • danazol
  • protease inhibitors

Antagonized by P450 inducers

  • carbamazepine, phenobarbital, phenytoin
  • rifabutin, rifampicin

Dosage and administration

Adminstration

  • enterally 12 hourly
  • continuous IV infusion
    • risk of anayphylaxis but may be used in short term if enteral administration is not possib;e
    • when switching from IV to enteral give first enteral dose 8-12 h after stopping infusion
  • give first dose no sooner than 6h after liver transplantation and with 24 h of kidney transplantation
  • when given as rescue therapy wait at least 24 h after stopping cyclosporin before giving tacrolimus

Dosage

  • enteral starting dose in adults: 0.1-0.3 mg/kg/day
  • lower dose in patients with renal or hepatic dysfunction
  • higher dose (per kg) in children
  • dose may reduced during maintenance therapy based on clinical assessment of rejection and tolerability for each patient
  • aim for whole blood trough level <20 mcg/l

Further reading

Scott et al. Tacrolimus. Drugs,2003;63(12):1247-97


 

©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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