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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
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