Tacrolimus

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Structural formula
Structural formula of tacrolimus
General
Non-proprietary name Tacrolimus
Molecular formula C 44 H 69 NO 12
External identifiers / databases
CAS number 104987-11-3
EC number 627-021-3
ECHA InfoCard 100.155.367
PubChem 445643
ChemSpider 393220
DrugBank DB00864
Wikidata Q411648
Drug information
ATC code

D11 AX14 , L04 AD02

Drug class
  • Immunosuppressant (systemic)
  • Immunomodulator (topical)
properties
Molar mass 804.02 g mol −1
Melting point

140 ° C

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic

danger

H and P phrases H: 301
P: 301 + 310
Toxicological data

134 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tacrolimus (also FK506 or FK-506) is a macrolide lactone from the gram-positive bacterium Streptomyces tsukubaensis . Tacrolimus is used as a drug from the group of immunomodulators or calcineurin inhibitors . Approval for clinical use in humans was first granted by the FDA in 1994 . Tacrolimus is used as a selective immunosuppressant against rejection reactions in organ transplants . Ointments containing tacrolimus are an alternative to topical glucocorticoids for atopic eczema and off-label for lichen sclerosus et atrophicus (LSA) and other dermatoses.

structure

It is a macrocyclic lactone with a molar mass of 822.05 Daltons . It was first isolated in 1987 by Japanese scientists from the culture medium of Streptomyces tsukubaensis. The extremely hydrophobic character of the molecule has important implications for therapeutic applications.

Mechanism of action

Tacrolimus is a substance with an immunosuppressive effect and belongs to the group of so-called calcineurin inhibitors. Tacrolimus specifically intervenes in signal transduction and in the activation of T cells . It binds to the cytosolic receptor, a so-called immunophilin (FKBP12) within the target cell. The complex of immunophilin and tacrolimus attaches to the serine threonine phosphatase calcineurin. Calcineurin can no longer be activated. As a result, the transcription and the release of cytokines (especially IL-2 , but also c-myc , IL-3 , TNFα , IFN-γ ) in the T cells are inhibited, whereby the reaction of the immune system to transplanted organs is suppressed. In terms of its mechanism of action, tacrolimus can be compared to ciclosporin , another calcineurin inhibitor.

use

  • On the one hand, tacrolimus is used systemically ( orally , in exceptional cases intravenously ) as an immunosuppressive agent in organ transplants in order to prevent the rejection of the transplanted organ after kidney, liver and heart transplants. It is also used to treat rejection when other immunosuppressants do not work.
  • It has also been reported that tacrolimus has been used in treatment-resistant forms of autoimmune diseases (e.g. ulcerative colitis , Crohn's disease , glomerulonephritis , myasthenia gravis ). It can also be taken at the same time as the start of azathioprine therapy, as the effect of azathioprine often only sets in several months after the start of therapy. Tacrolimus, on the other hand, works after a few days.
  • With tacrolimus there is also an ointment formulation for topical application that has been used successfully for the topical treatment of atopic eczema for over 10 years. It acts as an anti-inflammatory similar to the corticosteroids, but more selective than them. In contrast to corticosteroids, the entire class of “topical calcineurin inhibitors” tacrolimus and pimecrolimus do not cause the skin to thin and, unlike corticosteroids, do not increase intraocular pressure - other side effects must be observed. In addition to the classic “reactive” therapy of visible eczema foci, tacrolimus ointment has also been approved for long-term, “proactive” treatment - here the number of eczema flare-ups is reduced in the long term by minimal therapy (see Wollenberg et al.). It is also increasingly being used by dermatologists against vitiligo . This use is off label .

Side effects

This article or the following section is not adequately provided with supporting documents ( e.g. individual evidence ). Information without sufficient evidence could be removed soon. Please help Wikipedia by researching the information and including good evidence.

With regard to side effects , a distinction must be made between use as an immunosuppressant and as a topical drug for eczema. In the case of systemic use, nephrotoxicity and neurotoxicity should be mentioned . In patients with a donor kidney, nephrotoxicity can make a significant contribution to the development of chronic transplant nephropathy , so switching to another immunosuppressant that is not a calcineurin inhibitor may be indicated.

Immunosuppressive therapy increases the risk of developing cancer, with skin cancer being the most commonly reported. Immunosuppressed patients should therefore visit the dermatologist regularly and ensure adequate sun protection. Furthermore, neurological disorders such as tremor , dizziness, visual disturbances, depression and insomnia have been observed more frequently with tacrolimus ; also high blood pressure, convulsions, hypomagnesaemia , diabetes , loss of appetite, and hyperglycemia .

The degradation mechanism (cytochrome P450) also gives cause for caution in the case of multiple medication and the consumption of grapefruit juice .

Application to the skin very often causes burning, itching, flushing and redness in the first few days of treatment. Later, this can occur again shortly after consuming alcoholic beverages. Since there are theoretical reasons to believe that the dermal application of the risk for lymph node cancer ( lymphoma ) or a UV light-induced skin cancer could increase, these aspects will be given by scientists and lay press attention. Scientific studies that have examined the risk of both diseases with external tacrolimus use in atopic eczema, however, have so far not shown an increased cancer risk, but a statistically protective effect. The main risk factor for the development of lymphoma is the severity of the atopic eczema.

In February 2005, the FDA issued a health warning for topical tacrolimus drugs. The European health authority and the European eczema experts did not follow this opinion and promptly published a much more differentiated, clearly positive overall assessment of the tacrolimus ointment.

Tacrolimus ointment is approved from the age of two. The decision for treatment with tacrolimus ointment depends on numerous factors and requires a decision on a case-by-case basis. This also applies to the recently approved proactive therapy, in which long-term, minimal maintenance therapy for invisible minimal eczema is carried out to prevent eczema flare-ups.

In December 2008, Astellas sent a Rote-Hand-Brief : Application errors led to incorrect dosage of the preparations and thus to serious adverse reactions such as acute rejection of transplanted organs confirmed by biopsy and toxicity as a result of administration of too high doses. Immunosuppressive therapy requires a prescription and must be stopped by an experienced doctor.

Tacrolimus is an active ingredient with a narrow therapeutic range. The patients are individually adjusted to the immunosuppressive therapy based on the active level .

Trade names

Monopreparations
  • systemic: Advagraf (EU), Modigraf (EU), Prograf (EU), Envarsus (EU) and various generics [e.g. B. Tacpan, Tacrolimus HEXAL] (D, A)
  • topical: Protopic (D, A, CH)

literature

  • T. Kino, H. Hatanaka, M. Hashimoto et al: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physicochemical and biological characteristics. In: Journal of Antibiotics 40 (9), 1987, pp. 1249-1255; PMID 2445721 .
  • FM Arellano, CE Wentworth, A. Arana, C. Fernandez, CF Paul: Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. In: Journal of Investigative Dermatology . 127 (4), 2007, pp. 808-816.
  • DJ Margolis, O. Hoffstad, W. Bilker: Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. In: Dermatology . 214 (4), 2007, pp. 289-295.
  • T. Bieber, M. Cork, C. Ellis, G. Girolomoni, R. Groves, R. Langley et al: Consensus statement on the safety profile of topical calcineurin inhibitors. In: Dermatology. 211 (2), 2005, pp. 77-78.
  • U. Darsow, A. Wollenberg, D. Simon, A. Taieb, T. Werfel, A. Oranje et al: ETFAD / EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. In: Journal of the European Academy of Dermatology and Venereology . 2010, Volume 24, pp. 317-328.
  • A. Wollenberg, R. Frank, J. Kroth, T. Ruzicka: Proactive therapy of atopic eczema - an evidence-based therapy concept with a behavioral background. In: Journal of the German Dermatological Society . 7, 2009, pp. 117-121.
  • Ewout J Hoorn, Stephen B Walsh et al. a .: The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. In: Nature Medicine . 17, 2011, pp. 1304-1309, doi: 10.1038 / nm.2497 .

Web links

Individual evidence

  1. ↑ Shiva Pathak, Biki Gupta, Bijay Kumar Poudel, Tuan Hiep Tran, Shobha Regmi, Tung Thanh Pham, Raj Kumar Thapa, Min-Soo Kim, Chul Soon Yong, Jong Oh Kim, Jee-Heon Jeong: Preparation of High-Payload, Prolonged-Release Biodegradable Poly (lactic-co-glycolic acid) -Based Tacrolimus Microspheres Using the Single-Jet Electrospray Method in Chem. Pharm. Bull. 64 (2016) 171-178, doi : 10.1248 / cpb.c15-00799 .
  2. ↑ a b c data sheet FK-506 monohydrate from Sigma-Aldrich , accessed on April 23, 2011 ( PDF ).
  3. ↑ a b c www.ema.europa.eu Summary of the European Public Assessment Report (EPAR) (English)
  4. ↑ http://www.pharmazeutische-zeitung.de/index.php?id=27307 Vitiligo and treatment options
  5. ↑ VIVUS Announces Tacrolimus Receives Orphan Drug Designation in the European Union for the Treatment of Pulmonary Arterial Hypertension ( Memento of November 7, 2017 in the Internet Archive ), PM VIVUS of September 6, 2017, accessed on November 1, 2017
  6. ↑ Conversion of rejection prophylaxis to sirolimus - chance of maintaining kidney transplant function for longer. In: Dialysis News. 12, 2008, pp. 526-528, doi: 10.1055 / s-0028-1104662 .
  7. ↑ RK Wali, MR Weir: Chronic allograft dysfunction: can we use mammalian target of rapamycin inhibitors to replace calcineurin inhibitors to preserve graft function? In: Curr Opin Organ Transplant. 13, 2008, pp. 614-621. PMID 19060552 .
  8. ↑ JM Hanifin, AS Paller, L. Eichenfield, RA Clark, N. Korman, G. Weinstein, I. Caro, E. Jaracz, MJ Rico: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis . In: J. Am. Acad. Derm. 2005, 53, 2, 2, pp. 186-194. PMID 16021174 .
  9. ↑ www.fda.gov Tacrolimus FDA Health Warning (English)
  10. ^ NH Cox, Catherine H. Smith: Advice to dermatologists re topical tacrolimus. ( Memento of December 13, 2013 in the Internet Archive ) (PDF file; 10 kB). British Association of Dermatologists, Therapy Guidelines Committee, December 2002, accessed July 23, 2009.
  11. ↑ bfarm.de: Rote Hand Brief Advagraf® / Prograf®: Application error from December 2, 2008.