Clinical treatment of dry eye using 0.03% tacrolimus eye drops.

I wanted to add all the risks of Tacrolimus (Protopic) in the literature for patients who have been prescribed this by their dermatologist. 


Wilkipedia has a good review below as well: https://en.wikipedia.org/wiki/Tacrolimus




Tacrolimus (i.e., fujimycin or FK-506): Chemically tacrolimus is a 23-membered macrolide lacton macrolide (similary to many known antibiotics) that was first discovered in 1987 from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubaensis. It is an immunosuppressant used for liver transplant rejection prophylaxis and is under investigation for use in kidney, cardiac, pancreas, small bowel, and bone marrow transplantation. It is also used in a variety of autoimmune disease. Its mechanism of action is similar to that of cyclosporine, but with 10- to 100-fold greater potency.


In ophthalmology, topical tacrolimus is used in immune-mediated conditions to decrease inflammation, such as:
-ocular allergy: especially atopic conjunctivitis and blepharitis
-graft-versus-host disease, 
-corneal transplantation,
-ocular pemphigoid. 
-ocular Sjögren’s syndrome (used as 0.03% ophthalmic solution)
-keratoconjunctivitis sicca (used as 0.03% ophthalmic solution)






The risks include below (from Wiki):
I could not find any paper saying Tacrolimus worsens meibomian gland dysfunction.

Side effects[edit]

By mouth or intravenous use[edit]

Carcinogenesis and mutagenesis[edit]

Topical use[edit]

Cancer risks[edit]

Tacrolimus Ointment for Refractory Posterior Blepharitis.

Previous post: 




Tacrolimus is often prescribed for T cell-mediated diseases such as:
1. eczema or atopic dermatitis
2. psoriasis
3. Vitiligo

Orally Tacrolimus is used to:
1. prevent organ rejection
2. Uveitis after Bone Marrow transplantation
3. Minimal change disease of the kidney
4. Kimura’s disease

Allergic contact dermatitis from tacrolimus.

References:

https://www.jstage.jst.go.jp/article/bpb/41/11/41_b18-00056/_article

Abstract

Tacrolimus ointment is used worldwide to treat atopic dermatitis. Although tacrolimus ointment is not suitable for clinical admixtures, it is often mixed with various ointments or creams, such as corticosteroids, antibacterial agents, and moisturizing agents. There is only one report of quality testing of admixtures of tacrolimus ointment with adaparene gel (Differin® Gel). In this study, we used HPLC to evaluate the pharmaceutical stability of tacrolimus mixed with eight different dermatologic ointments or creams. No decrease in the tacrolimus content was observed in any of the mixtures after 4 weeks of storage at room temperature, indicating that tacrolimus admixtures are stable.

Graphical Abstract Fullsize Image

References (7)

• 1) Eto T. Usage of topical steroids-propriety of mixed prescription. Jpn. J. Clin. Dermat., 55, 96–101 (2001).





• 2) Japanese Dermatological Association. Guideline of care for the management of atopic dermatitis 2016. Jpn. J. Dermatol., 126, 121–155 (2016).





• 3) Interview Form of protopic ointment 0.1%, Maruho Co., Ltd., 2017.





• 4) Ohtani M. Effect of the admixture of commercially available corticosteroid ointments and/or creams on their efficacy and side effects. Jpn. J. Pharm. Health Care Sci., 29, 1–10 (2003), and references cited therein.





• 5) Ohtani M, Yamaoka Y, Matsumoto M, Namiki M, Yamamura Y, Etoh T. Compatibility of adaparene gel (Differin® Gel) with other kinds of ointments or creams. Yakuzaigaku, 69, 470–476 (2009).
• 6) https://en.wikipedia.org/wiki/Tacrolimus#targetText=Tacrolimus%2C%20also%20known%20as%20fujimycin,the%20risk%20of%20organ%20rejection.

Tacrolimus

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Tacrolimus

Clinical data
Trade names	Prograf, Advagraf, Protopic, others
Other names	FK-506, fujimycin
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Topical, oral, iv
ATC code	D11AH01 (WHO) L04AD02 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	24% (5–67%), less after eating food rich in fat
Protein binding	≥98.8%
Metabolism	Hepatic CYP3A4, CYP3A5
Elimination half-life	11.3 h for transplant patients (range 3.5–40.6 h)
Excretion	Mostly faecal
Identifiers
IUPAC name[show]
CAS Number	104987-11-3
PubChem CID	6473866
DrugBank	DB00864
ChemSpider	4976056
UNII	Y5L2157C4J
KEGG	DG00439
ChEBI	CHEBI:61049
ChEMBL	ChEMBL269732
CompTox Dashboard (EPA)	DTXSID5046354
ECHA InfoCard	100.155.367
Chemical and physical data
Formula	C44H69NO12
Molar mass	804.018 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[show]
InChI[show]
(what is this?)  (verify)

Tacrolimus, also known as fujimycin or FK506, is an immunosuppressive drug used mainly after allogeneic organ transplant to lower the risk of organ rejection. It achieves this by inhibiting calcineurin involved in the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, which are vital to the body’s learned (or adaptive) immune response. Tacrolimus is also used in the treatment of other T cell-mediated diseases such as eczema and psoriasis. (for which it is applied to the skin in a medicated ointment), severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, Kimura’s disease, and the skin condition vitiligo.

Chemically it is a 23-membered macrolide lactone that was first discovered in 1987 from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubaensis.

Tacrolimus is also used to treat dry eye syndrome in cats and dogs.^[1][2]

Contents

• 1Medical uses
  • 1.1Organ transplantation
  • 1.2Ulcerative colitis
  • 1.3Skin
• 2Contraindications and precautions
  • 2.1Topical use
• 3Side effects
  • 3.1By mouth or intravenous use
  • 3.2Topical use
• 4Interactions
• 5Pharmacology
  • 5.1Mechanism of action
  • 5.2Pharmacokinetics
  • 5.3Pharmacogenetics
• 6History
• 7Available forms
• 8Biosynthesis
• 9See also
• 10References
• 11External links

Medical uses[edit]

Organ transplantation[edit]

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.^[3] Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation.^[4][5] 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 such as basiliximab. Dosages are titrated to target blood levels.

Ulcerative colitis[edit]

In recent years, tacrolimus has been used to suppress the inflammation associated with ulcerative colitis (UC), 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 flares of UC.^[6][7]

Skin[edit]

Tacrolimus 0.1% ointment

See also: Medications used in treatment of eczema

As an ointment, tacrolimus is used in the treatment of eczema, in particular 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.^[8]

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.^{[citation needed]} 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.^[9]

Lupus Nephritis

Tacrolimus has been shown to reduce the risk of serious infection in lupus nephritis, when compared to other agents.^[10]

Contraindications and precautions[edit]

Contraindications and precautions include:^[11]

• Breast-feeding
• Hepatic disease
• Immunosuppression
• Infants
• Infection
• Neoplastic disease, such as:
  • Skin cancer
  • Lung cancer
• Oliguria
• Pregnancy
• QT interval prolongation
• Sunlight (UV) exposure
• Grapefruit juice^[12]

Topical use[edit]

• Occlusive dressing
• Known or suspected malignant lesions
• Netherton’s syndrome or similar skin diseases
• Certain skin infections^[8]

Side effects[edit]

By mouth or intravenous use[edit]

Side effects can be severe and include infection, cardiac damage, hypertension, blurred vision, liver and kidney problems (tacrolimus nephrotoxicity),^[13] hyperkalemia, hypomagnesemia, hyperglycemia, diabetes mellitus, itching, lung damage (sirolimus also causes lung damage),^[14] and various neuropsychiatric problems such as loss of appetite, insomnia, posterior reversible encephalopathy syndrome, confusion, weakness, depression, vivid nightmares, cramps, neuropathy, seizures, tremors, and catatonia.^[15]

In addition, it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections.^[11]

Carcinogenesis and mutagenesis[edit]

In people receiving immunosuppressants to reduce transplant graft rejection, an increased risk of malignancy (cancer) is a recognised complication.^[11] The most common cancers are non-Hodgkin’s lymphoma^{[citation needed]} and skin cancers. The risk appears to be related to the intensity and duration of treatment.

Topical use[edit]

The most common adverse events associated with the use of topical tacrolimus ointments, especially if used over a wide area, include a burning or itching sensation on the initial applications, with increased sensitivity to sunlight and heat on the affected areas. Less common are flu-like symptoms, headache, cough, and burning eyes.^[16]

Cancer risks[edit]

Further information: Eczema § Medications

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.^[17]

Interactions[edit]

Also like cyclosporin, it has a wide range of interactions. Tacrolimus is primarily metabolised by the cytochrome P450 system of liver enzymes, and there are many substances that interact with this system and induce or inhibit the system’s metabolic activity.^[11]

Interactions include that with grapefruit which increases tacrolimus plasma concentrations. As infections are a major cause of morbidity and mortality in the post-transplant patient, the most commonly^{[citation needed]} reported interactions include interactions with anti-microbial drugs. Macrolide antibiotics including erythromycin and clarithromycin, as well as several of the newer classes of antifungals, especially of the azole class (fluconazole, voriconazole), increase tacrolimus levels by competing for cytochrome enzymes.^[11]

Pharmacology[edit]

Mechanism of action[edit]

FKBP12, the target protein of tacrolimus

Tacrolimus is a macrolide calcineurin inhibitor. 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 nuclear factor of activated T-cells (NF-AT), 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.^[18]

In detail, tacrolimus reduces peptidylprolyl 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.^[19] Although this activity is similar to that of cyclosporin, the incidence of acute rejection is reduced by tacrolimus use over cyclosporin use.^[3] 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.^[20]

Pharmacokinetics[edit]

Oral tacrolimus is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and highest blood plasma concentrations (C_max) reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability. In the blood, tacrolimus is mainly bound to erythrocytes; only 5% are found in the plasma, of which more than 98.8% are bound to plasma proteins.^[11][21]

The substance is metabolized in the liver, mainly via CYP3A, and in the intestinal wall. All metabolites found in the circulation are inactive. Biological half-life varies widely and seems to be higher for healthy persons (43 hours on average) than for patients with liver transplants (12 hours) or kidney transplants (16 hours), due to differences in clearance. Tacrolimus is predominantly eliminated via the faeces in form of its metabolites.^[11][21]

When applied locally on eczema, tacrolimus has little to no bioavailability.^[11]

Pharmacogenetics[edit]

The predominant enzyme responsible for metabolism of tacrolimus is CYP3A5. Genetic variations within CYP3A5 that result in changes to the activity of the CYP3A5 protein can affect concentrations of tacrolimus within the body. In particular, individuals who are homozygous for the G allele at the single nucleotide polymorphism (SNP) rs776746 (also known as CYP3A5 *3/*3) have a non-functional CYP3A5 protein. The frequency of the G allele varies worldwide, from 4% in some African populations to 80–90% in Caucasian populations.^[22] Across a large number of studies, individuals homozygous for the G allele have been shown to have higher concentrations of tacrolimus and require lower doses of the drug, as compared to individuals who are not homozygous for the G allele. Achieving target concentrations of tacrolimus is important – if levels are too low, then there is a risk of transplant rejection, if levels are too high, there is a risk of drug toxicities. There is evidence to suggest that dosing patients based on rs776746 genotype can result in faster and more frequent achievement of target tacrolimus levels. However, there is a lack of consistent evidence as to whether dosing based on rs776746 genotype results in improved clinical outcomes (such as a decreased risk for transplant rejection or drug toxicities), likely because patients taking tacrolimus are subject to therapeutic drug monitoring.^{[23][24][25][26]}

Studies have shown that genetic polymorphisms of genes other than CYP3A5, such as NR1I2^[27][28] (encoding PXR), also significantly influence the pharmacokinetics of tacrolimus.

History[edit]

Tacrolimus was discovered in 1987;^[29] it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.^[30] It is produced by a soil bacterium, Streptomyces tsukubaensis.^[31] The name tacrolimus is derived from “Tsukuba macrolide immunosuppressant”.^[32]

Tacrolimus was first approved by the Food and Drug Administration 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.

Available forms[edit]

The branded version of the drug is owned by Astellas Pharma, and is sold under the trade name Prograf, given twice daily. A number of other manufacturers hold marketing authorisation for alternative brands of the twice-daily formulation.^[33]

Once-daily formulations with marketing authorisation include Advagraf (Astellas Pharma) and Envarsus (marketed as Envarsus XR in US by Veloxis Pharmaceuticals and marketed in Europe by Chiesi).^[33] These formulations are intended to reduce pharmacokinetic variation in blood levels and facilitate compliance with dosing.

The topical formulation is marketed by LEO Pharma under the name Protopic.^[33]

Biosynthesis[edit]

  

The biosynthesis of tacrolimus is hybrid synthesis of both type 1 polyketide synthases (PKS 1) and nonribosomal peptide synthases (NRPS). The research shows the hybrid synthesis consists of ten modules of type 1 polyketide synthase and one module of nonribosomal peptide synthase. The synthetic enzymes for tacrolimus are found in 19 gene clusters named fkb. The 19 genes are fkbQ, fkbN, fkbM, fkbD, fkbA, fkbP, fkbO, fkbB, fkbC, fkbL, fkbK, fkbJ, fkbI, fkbH, fkbG, allD, allR, allK and allA.^[34]

There are several possible ways of biosynthesis of tacrolimus. The fundamental units for biosynthesis are following: one molecule of 4,5-dihydroxycyclohex-1-enecarboxylic acid (DHCHC) as a starter unit, four molecules of malonyl-CoA, five molecules of methylmalonyl-CoA, one molecule of allylmalonyl-CoA as elongation units. However, two molecules of malonyl-CoA are able to be replaced by two molecules of methoxymalonyl CoA. Once two malonyl-CoA molecules are replaced, post-synthase tailoring steps are no longer required where two methoxymalonyl CoA molecules are substituted. The biosynthesis of methoxymalonyl CoA to Acyl Carrier protein is proceeded by five enzymes (fkbG, fkbH, fkbI, fkbJ, and fkbK). Allylmalonyl-CoA is also able to be replaced by propionylmalonyl-CoA.^[34]

The starter unit, DHCHC from the chorismic acid is formed by fkbO enzyme and loaded onto CoA-ligase domain (CoL). Then, it proceeds to NADPH dependent reduction(ER). Three enzymes, fkbA,B,C enforce processes from the loading module to the module 10, the last step of PKS 1. fkbB enzyme is responsible of allylmalonyl-CoA synthesis or possibly propionylmalonyl-CoA at C21, which it is an unusual step of general PKS 1. As mentioned, if two methoxymalonyl CoA molecules are substituted for two malonyl-CoA molecules, they will take place in module 7 and 8 (C13 and C15), and fkbA enzyme will enforce this process. After the last step (module 10) of PKS 1, one molecule of L–pipecolic acid formed from L–lysine and catalyzed through fkbL enzyme synthesizes with the molecule from the module 10. The process of L-pipecolic acid synthesis is NRPS enforced by fkbP enzyme. After synthesizing the entire subunits, the molecule is cyclized. After the cyclization, the pre-tacrolimus molecule goes through the post-synthase tailoring steps such as oxidation and S-adenosyl methionine. Particularly fkbM enzyme is responsible of alcohol methylation targeting the alcohol of DHCHC starter unit (Carbon number 31 depicted in brown), and fkbD enzyme is responsible of C9 (depicted in green). After these tailoring steps, the tacrolimus molecule becomes biologically active.^[34][35][36]

See also[edit]

• Tohru Kino
• Stuart Schreiber
• Thomas Starzl
• FK1012, a derivative
• Ciclosporin

References[edit]

1. ^ Berdoulay A, English RV, Nadelstein B (2005). “Effect of topical 0.02% tacrolimus aqueous suspension on tear production in dogs with keratoconjunctivitis sicca”. Veterinary Ophthalmology. 8 (4): 225–32. doi:10.1111/j.1463-5224.2005.00390.x. PMID 16008701.
2. ^ “Tacrolimus for Dogs and Cats”.
3. ^ Jump up to:^a b McCauley, Jerry (2004-05-19). “Long-Term Graft Survival In Kidney Transplant Recipients”. Slide Set Series on Analyses of Immunosuppressive Therapies. Medscape. Retrieved 2006-06-06.
4. ^ Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL (October 2006). McAlister V (ed.). “Cyclosporin versus tacrolimus for liver transplanted patients”. The Cochrane Database of Systematic Reviews. 4 (4): CD005161. doi:10.1002/14651858.CD005161.pub2. PMID 17054241.
5. ^ O’Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A (October 2002). “Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial”. Lancet. 360 (9340): 1119–25. doi:10.1016/S0140-6736(02)11196-2. PMID 12387959.
6. ^ Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU (May 2006). “Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease–a long-term follow-up”. The American Journal of Gastroenterology. 101 (5): 1048–56. doi:10.1111/j.1572-0241.2006.00524.x. PMID 16573777.
7. ^ Baumgart DC, Macdonald JK, Feagan B (July 2008). Baumgart DC (ed.). “Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis”. The Cochrane Database of Systematic Reviews. 16 (3): CD007216. doi:10.1002/14651858.CD007216. PMID 18646177.
8. ^ Jump up to:^a b Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Protopic.
9. ^ Silverberg NB, Lin P, Travis L, Farley-Li J, Mancini AJ, Wagner AM, Chamlin SL, Paller AS (November 2004). “Tacrolimus ointment promotes repigmentation of vitiligo in children: a review of 57 cases”. Journal of the American Academy of Dermatology. 51 (5): 760–6. doi:10.1016/j.jaad.2004.05.036. PMID 15523355.
10. ^ Singh JA, Hossain A, Kotb A, Wells G (September 2016). “Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis”. BMC Medicine. 14 (1): 137. doi:10.1186/s12916-016-0673-8. PMC 5022202. PMID 27623861.
11. ^ Jump up to:^{a b c d e f g h} Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Prograf.
12. ^ Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K (April 2006). “Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient”. Drug Metabolism and Pharmacokinetics. 21 (2): 122–5. doi:10.2133/dmpk.21.122. PMID 16702731.
13. ^ Naesens M, Kuypers DR, Sarwal M (February 2009). “Calcineurin inhibitor nephrotoxicity” (PDF). Clinical Journal of the American Society of Nephrology. 4 (2): 481–508. doi:10.2215/CJN.04800908. PMID 19218475.
14. ^ Miwa Y, Isozaki T, Wakabayashi K, Odai T, Matsunawa M, Yajima N, Negishi M, Ide H, Kasama T, Adachi M, Hisayuki T, Takemura T (2008). “Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis”. Modern Rheumatology. 18 (2): 208–11. doi:10.1007/s10165-008-0034-3. PMID 18306979.
15. ^ O’Donnell MM, Williams JP, Weinrieb R, Denysenko L (2007). “Catatonic mutism after liver transplant rapidly reversed with lorazepam”. General Hospital Psychiatry. 29 (3): 280–1. doi:10.1016/j.genhosppsych.2007.01.004. PMID 17484951.
16. ^ Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ (August 2005). “Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis”. Journal of the American Academy of Dermatology. 53 (2 Suppl 2): S186–94. doi:10.1016/j.jaad.2005.04.062. PMID 16021174.
17. ^ N H Cox & Catherine H Smith (December 2002). “Advice to dermatologists re topical tacrolimus” (PDF). Therapy Guidelines Committee. British Association of Dermatologists. Archived from the original (PDF) on 2013-12-13.
18. ^ William F. Ganong (2005-03-08). Review of medical physiology(22nd ed.). Lange medical books. p. 530. ISBN 978-0-07-144040-0.
19. ^ Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (August 1991). “Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes”. Cell. 66 (4): 807–15. doi:10.1016/0092-8674(91)90124-H. PMID 1715244.
20. ^ Abou-Jaoude MM, Najm R, Shaheen J, Nawfal N, Abboud S, Alhabash M, Darwish M, Mulhem A, Ojjeh A, Almawi WY (September 2005). “Tacrolimus (FK506) versus cyclosporine microemulsion (neoral) as maintenance immunosuppression therapy in kidney transplant recipients”. Transplantation Proceedings. 37 (7): 3025–8. doi:10.1016/j.transproceed.2005.08.040. PMID 16213293.
21. ^ Jump up to:^a b Dinnendahl, V; Fricke, U, eds. (2003). Arzneistoff-Profile (in German). 9 (18 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
22. ^ Bains, Ripudaman Kaur. “Molecular diversity and population structure at the CYP3A5 gene in Africa” (PDF). University College London. Retrieved 13 June 2016.
23. ^ Staatz CE, Tett SE (2004). “Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation”. Clinical Pharmacokinetics. 43 (10): 623–53. doi:10.2165/00003088-200443100-00001. PMID 15244495.
24. ^ Staatz CE, Goodman LK, Tett SE (March 2010). “Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I”. Clinical Pharmacokinetics. 49 (3): 141–75. doi:10.2165/11317350-000000000-00000. PMID 20170205.
25. ^ Staatz CE, Goodman LK, Tett SE (April 2010). “Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II”. Clinical Pharmacokinetics. 49 (4): 207–21. doi:10.2165/11317550-000000000-00000. PMID 20214406.
26. ^ Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB (October 2013). “PharmGKB summary: cyclosporine and tacrolimus pathways”. Pharmacogenetics and Genomics. 23(10): 563–85. doi:10.1097/fpc.0b013e328364db84. PMC 4119065. PMID 23922006.
27. ^ Benkali K, Prémaud A, Picard N, Rérolle JP, Toupance O, Hoizey G, Turcant A, Villemain F, Le Meur Y, Marquet P, Rousseau A (2009-01-01). “Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients”. Clinical Pharmacokinetics. 48 (12): 805–16. doi:10.2165/11318080-000000000-00000. PMID 19902988.
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Br J Dermatol. 2008 Sep;159(4):942-51. doi: 10.1111/j.1365-2133.2008.08747.x. Epub 2008 Jul 15.

A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients.

Reitamo S1, Rustin M, Harper J, Kalimo K, Rubins A, Cambazard F, Brenninkmeijer EE, Smith C, Berth-Jones J, Ruzicka T, Sharpe G, Taieb A; 0.1% Tacrolimus Ointment Long-term Follow-up Study Group.

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Abstract

BACKGROUND:

For the treatment of a chronic disease like atopic dermatitis, sustained tolerability and efficacy of the applied medication are essential.

OBJECTIVES:

The present open-label, noncomparative study was conducted to obtain information on the long-term safety and efficacy of 0.1% tacrolimus ointment.

METHODS:

Patients aged 2 years or older with an affected body surface area of more than 5%, who previously participated in a clinical trial on tacrolimus ointment, were eligible for this study. The treatment area was defined by the investigator at study entry. Both children and adults applied continuously or intermittently 0.1% tacrolimus ointment twice daily during episodes of active disease plus an additional week after remission over a follow-up period of up to 4 years.

RESULTS:

The intent-to-treat population comprised 782 patients, with a median age of 22 years (range 2-72). Patients remained in the study for up to 4 years. Approximately half of the patients discontinued the study prematurely; the median follow-up was 1422 days. Median tacrolimus ointment use was 31.2 g during the first week; ointment use decreased during the first year and then remained stable for the remainder of the study. The median cumulative tacrolimus use was 271.5 g at month 6, 462.5 g at month 12, 739.9 g at month 24, 1029.3 g at month 36 and 1320.8 g at month 48. Altogether 51.8% of patients discontinued the study prematurely; the main reasons were withdrawal of consent (13.3%), loss to follow-up (11.3%) and lack of efficacy (9.4%). Adverse events led to study discontinuation in 3.7% of the patients. The most frequent application site events were skin burning and pruritus. These events were most often reported in adult patients during the initial treatment period; prevalence decreased after the first week and remained at a low level throughout the study. Nonapplication site events occurred with stable incidences throughout the study period. In general, calculated daily hazard rates did not indicate an increased risk of adverse events with prolonged treatment. The total affected body surface area decreased substantially upon onset of treatment and efficacy of treatment was maintained until the end of the study with smaller but continuous improvements throughout the follow-up period. Overall, 75% of the patients and 76% of the investigators rated their satisfaction with the treatment as excellent, very good or good at the end of the study or at the time of premature discontinuation.

CONCLUSIONS:

The safety profile of intermittent or continuous long-term application of 0.1% tacrolimus ointment for up to 4 years was consistent with that which has been established from shorter studies and gave no reason for concern. In addition, 0.1% tacrolimus ointment demonstrated sustained efficacy as reflected by the expression of high satisfaction with treatment by both patients and investigators.

Journal of the American Academy of Dermatology

Volume 53, Issue 2, Supplement 2, August 2005, Pages S186-S194

Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis

Author links open overlay panelJon M.HanifinMDaAmy S.PallerMDbLawrenceEichenfieldMDcRichard A.ClarkMDdNeilKormanMD, PhDeGeraldWeinsteinMDfIvorCaroMDgEileenJaraczPharmDhM. JoyceRicoMDhfor the US Tacrolimus Ointment Study Group∗

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Objective

This study was designed to evaluate the long-term safety and efficacy of 0.1% tacrolimus ointment in adult and pediatric patients with atopic dermatitis (AD).

Methods

A total of 408 adult and 391 pediatric patients with AD who had participated in a previous clinical trial of tacrolimus ointment were enrolled in this long-term, open-label, noncomparative trial. Tacrolimus ointment 0.1% was applied twice daily either intermittently or continuously to the affected areas. Efficacy and safety assessments included percent body surface area affected, Eczema Area and Severity Index score, individual signs of AD, and the incidence of adverse events.

Results

A total of 799 patients were evaluated, of whom 300 (37.5%) were followed for more than 3 years (maximum 49 months). Improvements in efficacy parameters were observed within 1 week of treatment and continued for the duration of the study. Common adverse events included skin burning, pruritus, skin infection, skin erythema, flu-like symptoms, and headache. The incidence of adverse events, including cutaneous infections, did not increase with time on study.

Conclusion

Tacrolimus ointment therapy is a rapidly effective and safe treatment for the management of AD in pediatric and adult patients for up to 4 years.

ELECTRONIC ARTICLES

Tacrolimus Ointment 0.03% Is Safe and Effective for the Treatment of Mild to Moderate Atopic Dermatitis in Pediatric Patients: Results From a Randomized, Double-Blind, Vehicle-Controlled Study

Lawrence A. Schachner, Cindy Lamerson, Mary P. Sheehan, Mark Boguniewicz, Joy Mosser, Sharon Raimer, Toni Shull, Eileen Jaracz and ; for the US Tacrolimus Ointment Study Group

Pediatrics September 2005, 116 (3) e334-e342; DOI: https://doi.org/10.1542/peds.2004-2638

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Abstract

Objective. This study was designed to compare the safety and efficacy of tacrolimus ointment 0.03% with vehicle ointment for the treatment of mild to moderate atopic dermatitis (AD) in pediatric patients.

Methods. A total of 317 patients (2–15 years of age) with mild to moderate AD were randomized to receive tacrolimus ointment or vehicle ointment twice daily in a 6-week, multicenter, double-blind study. Efficacy evaluations, including the Investigators’ Global Atopic Dermatitis Assessment, eczema area and severity index, percentage of total body surface area affected, and patient assessment of itch occurred at baseline, day 4, and weeks 2, 4, and 6. Cutaneous adverse events were recorded to evaluate safety.

Results. At the end of study, 50.6% (80 of 158) of the patients were treated successfully with tacrolimus ointment based on Investigators’ Global Atopic Dermatitis Assessment scores, a significant improvement compared with patients treated with vehicle ointment (25.8% [41 of 159]). The percent improvement from baseline in eczema area and severity index scores was also significantly greater in tacrolimus-treated patients (54.8%) compared with vehicle-treated patients (20.8%). There was also a significant improvement in the percentage of total body surface area affected of tacrolimus-treated patients (50.5% reduction from baseline) compared with vehicle-treated patients (16.4%). Patient itch scores were significantly lower in tacrolimus-treated patients (2.1) versus vehicle-treated patients (3.7). Overall, the incidence of cutaneous adverse events reported was similar for both treatment groups. There was no significant difference in the incidence of burning or stinging between treatment groups. Significantly fewer tacrolimus-treated patients prematurely discontinued from the study because of a cutaneous adverse event in the treatment area or experienced increased itching and erythema at the application site.

Conclusion. Monotherapy with tacrolimus ointment 0.03% is a safe and effective treatment alternative for pediatric patients with mild to moderate AD.