| Systematic (IUPAC) name | |
|---|---|
| 3S-[3R*[E(1S*,3S*,4S*)] ,4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR* |
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| Clinical data | |
| Pregnancy cat. | C |
| Legal status | ? |
| Routes | Topical, oral, iv |
| Pharmacokinetic data | |
| Bioavailability | 20%, less after eating food rich in fat |
| Protein binding | 75-99% |
| Metabolism | Hepatic CYP3A4 |
| Half-life | 11.3 h (range 3.5-40.6 h) |
| Excretion | Mostly faecal |
| Identifiers | |
| CAS number | 104987-11-3 |
| ATC code | D11AH01 L04AD02 |
| PubChem | CID 6473866 |
| DrugBank | DB00864 |
| ChemSpider | 4976056 |
| UNII | Y5L2157C4J |
| ChEMBL | CHEMBL1200738 |
| Chemical data | |
| Formula | C44H69NO12 |
| Mol. mass | 804.018 g/mol |
| SMILES | eMolecules & PubChem |
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Tacrolimus (also FK-506 or fujimycin, trade names Prograf, Advagraf, Protopic) is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection. It is also used in a topical preparation in the treatment of atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, and the skin condition vitiligo.
It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. It reduces interleukin-2 (IL-2) production by T-cells.
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Tacrolimus was discovered in 1984; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.[1] Like ciclosporin, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis.[2] The name tacrolimus is derived from 'Tsukuba macrolide immunosuppressant'.[3]
Tacrolimus was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.
The branded version of the drug is owned by Astellas Pharma, and is sold under the trade names Prograf given twice daily, Advagraf, a sustained release formulation allowing once daily dosing, and Protopic (Eczemus in Pakistan by Brookes Pharma), the topical formulation.[4] Advagraf is available in 0.5, 1, 3 and 5 mg capsules, the ointment is concentrations of 0.1% and 0.03%.
A second once-daily formulation of tacrolimus is in Phase 3 clinical trials in the U.S. and Europe. This formulation also has a smoother pharmacokinetic profile that reduces the peak-to-trough range in blood levels compared to twice-daily tacrolimus.[5] Data from the first Phase 3 trial in stable kidney transplant patients showed that this once-daily formulation was non-inferior in efficacy and safety compared to twice-daily tacrolimus.[6] A second Phase 3 trial in de novo patients is ongoing.[7]
Tacrolimus is chemically known as a macrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT.[8] In detail, Tacrolimus reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.[9] Although this activity is similar to ciclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin.[10] Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival.[11]
It has similar immunosuppressive properties to ciclosporin, but is much more potent. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with ciclosporin-based immunosuppression (30.7% vs 46.4%) in one study.[10] Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation.[12][13] Long term outcome has not been improved to the same extent. Tacrolimus is normally prescribed as part of a post-transplant cocktail including steroids, mycophenolate and IL-2 receptor inhibitors. Dosages are titrated to target blood levels. Typical starting doses for once daily tacrolimus are 0.15-0.20 mg/kg.
Also like ciclosporin it has a wide range of interactions, including that with grapefruit which increases plasma-tacrolimus concentration. Several of the newer class of antifungals, especially of the azole class (fluconazole, posaconazole) also increase drug levels by competing for degradative enzymes.
In recent years, Tacrolimus has been used to suppress the inflammation associated with ulcerative colitis, a form of inflammatory bowel disease. Although almost exclusively used in trial cases only, Tacrolimus has shown to be significantly effective in the suppression of outbreaks of UC.[14][15]
As an ointment (Protopic), tacrolimus is used in the treatment of eczema, particularly atopic dermatitis. It suppresses inflammation in a similar way to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that unlike steroids, it does not cause skin thinning (atrophy), or other steroid related side-effects.
It is applied on the active lesions until they heal off, but may also be used continuously in low doses (twice a week), and applied to the thinner skin over the face and eyelids. Clinical trials of up to one year have been conducted. Recently it has also been used to treat segmental vitiligo in children, especially in areas on the face.[16]
Side effects can be severe and include infection, cardiac damage, hypertension, blurred vision, liver and kidney problems (tacrolimus nephrotoxicity),[17] hyperkalemia, hypomagnesemia, hyperglycemia, diabetes mellitus, itching, lung damage (sirolimus also causes lung damage),[18] and various neuropsychiatric problems such as loss of appetite, insomnia, Posterior reversible encephalopathy syndrome, confusion, weakness, depression, cramps, neuropathy, seizures, tremors, and catatonia.[19]
In addition it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections.
In people receiving immunosuppressants to reduce transplant graft rejection, an increase risk of malignancy is a recognised complication. The commonest cancers are non-Hodgkin's lymphoma and skin cancers. The risk appears to be related to the intensity and duration of treatment.
The most common adverse events associated with the use of Protopic, especially if used over a wide area, include a burning or itching sensation on the initial applications. Less common are flu-like symptoms, headache and cough and burning eyes.[20]
The use of Protopic should be avoided on known or suspected malignant lesions. The use of Protopic on patients with Netherton's syndrome or similar skin diseases is not recommended. Patients should minimize or avoid natural or artificial sunlight exposure. Skin infections should be cleared prior to application, and there may be an increased risk of certain skin infections. Protopic should not be used with occlusive dressings (http://www.protopic.com/).
Tacrolimus and a related drug for eczema (pimecrolimus) were suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the drug, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. However, current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.[21]
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