Tacrolimus (TACR), previously known as FK-506, is a macrocyclic lactone antibiotic that was initially extracted in Japan from the soil microorganism, Streptomyces tsukubaensis, in 1984.1,2 The drug, which is a calcineurin inhibitor, was granted approval by the U.S. Food and Drug Administration (FDA) for preventing rejection after liver (1994), kidney (1997), and heart transplants (2006).1,3
Mechanism of Action
Tacrolimus, a potent inhibitor of T-lymphocyte proliferation, binds to the FK-binding protein (FKBP), which is an intracellular cytoplasmic immunophilin.2 The tacrolimus-FKBP complex inhibits the calcium-dependent phosphatase, calcineurin, which leads to the inhibition of T-cell activation, resulting in immunosuppression.2, 4
TACR, which is similar to cyclosporine, but 100 times more potent,5 is mainly indicated for the following:
- Prevention of transplant rejection
- As a substitute to cyclosporine for primary immunosuppression following solid organ transplantation2
- As a rescue therapy in patients with refractory rejection with cyclosporine treatment
- Prophylaxis against host-versus-graft disease
- Topical therapy for atopic dermatitis, scleroderma, and other eczematous diseases6
- Suppressing inflammation in inflammatory bowel disease, severe steroid-refractory or steroid-dependent ulcerative colitis, and Crohn’s disease.7,8
- Nephrotoxicity and neurotoxicity
- Lightheadedness and blurred vision
- Enhanced risk for developing cancer, diabetes mellitus, hypertension, dysrhythmias, and left ventricular hypertrophy with heart failure
- Other associated side effects such as weight gain, hair loss, itching, diarrhea, dyspepsia, vomiting, etc10
CYP3A gene and P-glycoprotein play a key role in tacrolimus metabolism. Administration of tacrolimus with other drugs or substances that are also metabolized by the same gene and protein can alter the blood concentrations of the drug.
Substances Interfering with Tacrolimus Blood Levels
Substances that increase tacrolimus levels
Substances that decrease tacrolimus levels
Antibiotics and Antifungal drugs: clarithromycin, erythromycin clotrimazole, fluconazole
Antibiotics: rifabutin, rifampin
Calcium channel blockers: diltiazem, nifedipine
Anticonvulsants: carbamazepine, phenytoin
Other substances: antacids, St. John’s wort
Gastrointestinal prokinetic agents: cisapride
Other immunosuppressants: cyclosporine
Other substances: grapefruit juice
Dosage and Administration
TACR is generally administered orally, intravenously, or sublingually.2 The required dose is lower compared to cyclosporine due to its higher potency.4
Monitoring of Tacrolimus Levels
Tacrolimus has a low therapeutic index with a high inter-and intra-pharmacokinetic variability, and possesses several side effects and drug interactions.11 All these factors necessitate individualized monitoring of the drug levels in blood. The therapeutic drug monitoring (TDM) methods generally followed include:
- Trough concentration (C0) monitoring
- Area under the curve (AUC ) monitoring
Monitoring, initiated on the second or third day of therapy, is continued for the first 2 weeks, 3-7 times per week; with a gradual reduction in the monitoring frequency. Some key points to note while monitoring TACR include:12
- Peak TACR levels in whole blood are achieved about 1-2 hours following oral administration
- The cornerstone of TACR evaluation is the trough level obtained 12 hours after the administration of the drug. This measurement provides a good indication of the total drug exposure.13
- Studies have found that AUC0-12h correlates well with 12-hour trough levels.4 To overcome the limitations of multiple sampling involved in AUC monitoring, an abbreviated AUC approach has evolved. This involves the evaluation of at least 2 samples collected between 0-4 hours after drug administration.
Enduring Expertise for Your Immunosuppressant Drug Testing Needs
Learn more about the tacrolimus assays available on the following instruments:
- 1 Schuurman H-J. Modern Immunosuppressives. Birkhäuser. 2001:29.
- 2 Franco KL. Advanced Therapy in Thoracic Surgery. PMPH-USA. 2005:349.
- 3 Astellas Pharma, Inc. Astellas Receives an FDA Action Letter for Prograf’s NDA. Accessed February 2009.
- 4 Davison AM. Oxford Textbook of Clinical Nephrology. Oxford University Press. 2005:2060.
- 5 Bishop ML. Clinical Chemistry: Principles, Procedures, Correlations. Lippincott Williams & Wilkins. 2004:583.
- 6 Golan DE. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. 2008:803.
- 7 Baumgart DC, et al. Am J Gastroenterol. 2006;101:1048-56.
- 8 Baumgart DC, et al. Cochrane Database Syst Rev. 2008;CD007216.
- 9 Aschenbrenner DS. Drug Therapy in Nursing. Lippincott Williams & Wilkins. 2008:664.
- 10 Palmer M. Dr. Melissa Palmer's Guide to Hepatitis & Liver Disease: What You Need to Know. Avery. 2004:374.
- 11 Yargui L, et al. Ann Biol Clin (Paris). 2008;66:657-64.
- 12 Burton ME. Applied Pharmacokinetics & Pharmacodynamics: Principles of Therapeutic Drug Monitoring. Lippincott Williams & Wilkins. 2005:552.
- 13 Tiwari P, et al. Indian Journal of Pharmacology. 2007;39:66-70.