Pimecrolimus is an
immunomodulating agent of the
calcineurin inhibitor class used in the treatment of
atopic dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin ( dermatitis). It results in itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thickens over tim ...
(eczema). It is available as a topical cream, once marketed by
Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-lo ...
(however,
Galderma
Galderma S.A. is a Swiss pharmaceutical company specializing in dermatological treatments and skin care products. Formerly a subsidiary of L'Oréal and Nestlé, it has been held by a consortium of private institutional investors since 2019.
...
has been promoting the compound in Canada since early 2007) under the trade name Elidel.
Medical uses
It has been proven to be effective in various
inflammatory skin diseases, e.g.,
seborrheic dermatitis,
cutaneous lupus erythematosus
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different de ...
,
oral lichen planus
Lichen planus (LP) is a chronic inflammatory and immune-mediated disease that affects the skin, nails, hair, and mucous membranes. It is not an actual lichen, and is only named that because it looks like one. It is characterized by polygonal, fl ...
,
vitiligo
Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes.
Signs and symptoms
The only sign of vitiligo is the presence of pale patchy areas of depigmen ...
, and
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to comple ...
. Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants.
Side effects
In January 2006, the United States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) announced that Elidel packaging would be required to carry a
black box warning
In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because
the U.S. Food and Drug Administration specifies that i ...
regarding the potential increased risk of
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
or
skin cancer
Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
, as for the similar drug
tacrolimus, whereas current practice by
UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.
Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the
American Academy of Dermatology
The American Academy of Dermatology (AAD) is a non-profit professional organization of dermatologists in the United States and Canada, based in Rosemont, Illinois, near Chicago. It was founded in 1938 and has more than 20,500 members. The Academ ...
Association Task Force finds that there is no causal proof that topical immunomodulators cause
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
or nonmelanoma
skin cancer
Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism. Another recent review of evidence concluded that
postmarketing surveillance Postmarketing surveillance (PMS), also known as post market surveillance, is the practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released on the market and is an important part of the science of pharmac ...
shows no evidence for this systemic immunosuppression or increased risk for any malignancy.
However, strong debates and controversies continue regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials.
Dermatologists' and allergists' professional societies, the
American Academy of Dermatology
The American Academy of Dermatology (AAD) is a non-profit professional organization of dermatologists in the United States and Canada, based in Rosemont, Illinois, near Chicago. It was founded in 1938 and has more than 20,500 members. The Academ ...
, and the
American Academy of Allergy, Asthma, and Immunology, have protested the inclusion of the black box warning. The AAAAI states "None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship."
Pharmacology
Pimecrolimus is an
ascomycin macro
lactam
A lactam is a cyclic amide, formally derived from an amino alkanoic acid. The term is a portmanteau of the words '' lactone'' + ''amide''.
Nomenclature
Greek prefixes in alphabetical order indicate ring size:
* α-Lactam (3-atom rings)
* β-Lac ...
derivative. It has been shown ''in vitro'' that pimecrolimus binds to
FKBP1A
Peptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the ''FKBP1A'' gene.
Function
The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basi ...
and also inhibits
calcineurin
Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be block ...
. Thus pimecrolimus inhibits
T-cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
activation by inhibiting the synthesis and release of
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s.
Pimecrolimus, like
tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
, thereby preventing the cascade of immune and inflammatory signals.
Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells. It has lower permeation through the skin than topical steroids or topical
tacrolimus although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy.
References
External links
FDA NewsArticle about American Academy of Dermatology speaking out against black box warningReport of the Calcineurin Task Force of the ACAAI and AAAAI
{{Other dermatological preparations
Disulfiram-like drugs
Immunosuppressants
Macrolides
Novartis brands