Oclacitinib

Last updated
Oclacitinib
Oclacitinib.svg
Apoquel bottle.jpg
Clinical data
Trade names Apoquel
Other namesPF-03394197
AHFS/Drugs.com Veterinary Use
Routes of
administration 		By mouth
Drug class JAK inhibitor
ATCvet code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 89% [1]
Protein binding 66.3–69.7% [1]
Metabolism Liver [1]
Elimination half-life 3.1–5.2 hours [1]
Excretion Mostly liver [1]
Identifiers
  • N-Methyl{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclohexyl}methanesulfonamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C15H23N5O2S
Molar mass 337.44 g·mol−1
3D model (JSmol)
  • CNS(=O)(=O)C[C@@H]1CC[C@H](CC1)N(C)c2[nH]cnc3nccc23
  • InChI=1S/C15H23N5O2S/c1-16-23(21,22)9-11-3-5-12(6-4-11)20(2)15-13-7-8-17-14(13)18-10-19-15/h7-8,10-12,16H,3-6,9H2,1-2H3,(H,17,18,19)/t11-,12-
  • Key:HJWLJNBZVZDLAQ-HAQNSBGRSA-N


Oclacitinib, sold under the brand name Apoquel among others, is a veterinary medication used in the control of atopic dermatitis and pruritus from allergic dermatitis in dogs at least 12 months of age. [1] [3] Chemically, it is a synthetic cyclohexylamino pyrrolopyrimidine janus kinase inhibitor that is relatively selective for JAK1. [4] It inhibits signal transduction when the JAK is activated and thus helps downregulate expression of inflammatory cytokines.[ medical citation needed ]

Contents

Oclacitinib was approved for use in the United States in 2013, [3] and in the European Union in 2023. [2] [5]

Uses

Oclacitinib is labeled to treat atopic dermatitis and itchiness (pruritus) caused by allergies in dogs, though it has also been used to reduce the itchiness and dermatitis caused by flea infestations. [6] [7] It is considered to be highly effective in dogs, and has been established as safe for at least short-term use. [8] [9] [10] Its efficacy equals that of prednisolone at first, though oclacitinib has been found to be more effective in the short term in terms of itchiness and dermatitis, long term safety is unknown. [11] It has been found to have a faster onset and cause less gastrointestinal issues than cyclosporine. [9] [12]

While safe in the short term, oclacitinib's long-term safety is unknown. [9] [13] While some say it is best only for acute flares of itchiness, others claim that it is also useful in chronic atopic dermatitis. [7] [13]

There is some off-label use of oclacitinib in treating asthma and allergic dermatitis in cats, but the exact efficacy has not been established. [11] [7]

Contraindications

Oclacitinib is not labeled for use in dogs younger than one due to reports of it causing demodicosis. [12] It should also be avoided in dogs less than 3 kg (6.6 lb). Most of the other contraindications are avoiding cases where a potential side effect exacerbates a pre-existing condition: for example, because oclacitinib can cause lumps or tumors, it should not be used in dogs with cancer or a history of it; [14] because it is an immune system suppressant, it should not be used in dogs with serious infections. [9]

Oclacitinib, by virtue of its low plasma protein binding, has little chance of reacting with other drugs. Nonetheless, concurrent use of steroids and oclacitinib has not been tested and is thus not recommended. [9]

Side Effects

Oclacitinib lacks the side effects that most JAK inhibitors have in humans; instead, side effects are infrequent, mild, and mostly self-limiting. [12] [13] [15] The most common side effects are gastrointestinal problems (vomiting, diarrhea, and appetite loss) and lethargy. The GI problems can sometimes be alleviated by giving oclacitinib with food. [9] [14] New cutaneous or subcutaneous lumps, such as papillomas, can appear, [9] [16] and dogs face an increased susceptibility to infections such as demodicosis. [1] [14] There is a transient decrease in neutrophils, eosinophils, and monocytes, as well as in serum globulin, while cholesterol and lipase levels increase. The decrease in white blood cells lasts only around 14 days. None of the increases or decreases are clinically significant (i.e. none push their corresponding values out of normal ranges). [1] [16] [17]

Less common side effects of oclacitinib include bloody diarrhea; pneumonia; infections of the skin, ear, and/or urinary tract; and histiocytomas (benign tumors). Increases in appetite, aggression, and thirst have also been reported. [9] [14]

Pharmacodynamics

Mechanism of Action

Oclacitinib is not a corticosteroid or antihistamine, but rather modulates the production of signal molecules called cytokines in some cells. [12] Normally, a cytokine binds to a JAK (Janus kinase) receptor, driving the two individual chains to come together and self-phosphorylate. This brings in STAT proteins, which are activated and then go to the nucleus to increase transcription of genes coding for cytokines, thus increasing cytokine production. [18]

Oclacitinib inhibits signal JAK family members (JAK1, JAK2, JAK3, and tyrosine kinase 2), most effectively JAK1, while not significantly inhibiting non-JAK kinases. [4] [18]

ReceptorMean IC50 (nM)
JAK1 10
JAK2 18
JAK3 99
TYK2 84

This causes the inhibition of pro-inflammatory and pruritogenic (itch-causing) cytokines that depend on JAK1 and JAK3, which include IL-2, IL-4, IL-6, IL-13, and IL-31 [1] [11] [12] (TSLP, another pruritogenic cytokine that uses JAKs, has also been found to be inhibited). [19] [20] IL-31 is a key cytokine at the pruritogenic receptors at neurons near the skin, and also induces peripheral blood mononuclear cells and keratinocytes to release pro-inflammatory cytokines. [15] Suppression of IL-4 and IL-13 causes a decrease of Th2-cell differentiation, which plays a role in atopic dermatitis. [18] Oclacitinib's relatively little effect on JAK2 prevent it from suppressing hematopoiesis or the innate immune response. [6] [12]

Oclacitinib inhibits JAK, not the pruritogenic cytokines themselves; studies in mice showed that suddenly stopping the medication caused an increase in itchiness caused by a rebound effect, where more cytokines were produced to overcome lack of response by JAK. [20]

Pharmacokinetics

Oclacitinib is absorbed well when taken orally; it takes less than an hour to reach peak plasma concentration and has a bioavailability of 89%. [1] In most dogs, pruritus begins to subside within four hours and is completely gone within 24. Oclacitinib is cleared mostly by being metabolized in the liver, though there is some kidney and bile duct clearance as well. [1]

Related Research Articles

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

<span class="mw-page-title-main">Dermatitis</span> Inflammation of the skin

Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can vary from small to covering the entire body. Dermatitis is often called eczema, and the difference between those terms is not standardized.

<span class="mw-page-title-main">Itch</span> Sensation that causes desire or reflex to scratch

Itch is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response patterns are different. Pain creates a withdrawal reflex, whereas itches leads to a scratch reflex.

<span class="mw-page-title-main">Demodicosis</span> Medical condition

Demodicosis, also called Demodex folliculitis in humans and demodectic mange or red mange in animals, is caused by a sensitivity to and overpopulation of Demodex spp. as the host's immune system is unable to keep the mites under control.

Antipruritics, abirritants, or anti-itch drugs, are medications that inhibit the itching often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, fungal infections, insect bites and stings like those from mosquitoes, fleas, and mites, and contact dermatitis and urticaria caused by plants such as poison ivy or stinging nettle. It can also be caused by chronic kidney disease and related conditions.

Skin disorders are among the most common health problems in dogs, and have many causes. The condition of a dog's skin and coat is also an important indicator of its general health. Skin disorders of dogs vary from acute, self-limiting problems to chronic or long-lasting problems requiring life-time treatment. Skin disorders may be primary or secondary in nature, making diagnosis complicated.

<span class="mw-page-title-main">Atopic dermatitis</span> Long-term form of skin inflammation

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 can thicken over time. AD may also simply be called eczema, a term that generally refers to a larger group of skin conditions.

<span class="mw-page-title-main">Avenanthramide</span> Type of alkaloid

Avenanthramides are a group of phenolic alkaloids found mainly in oats, but also present in white cabbage butterfly eggs, and in fungus-infected carnation. A number of studies demonstrate that these natural products have anti-inflammatory, antioxidant, anti-itch, anti-irritant, and antiatherogenic activities. Oat kernel extracts with standardized levels of avenanthramides are used for skin, hair, baby, and sun care products. The name avenanthramides was coined by Collins when he reported the presence of these compounds in oat kernels. It was later found that three avenanthramides were the open-ring amides of avenalumins I, II, and III, which were previously reported as oat phytoalexins by Mayama and co-workers.

<span class="mw-page-title-main">Hydrocortisone aceponate</span> Chemical compound

Hydrocortisone aceponate is a veterinary corticosteroid that is used in form of creams for the treatment of various dermatoses. It is an ester of hydrocortisone (cortisol) with acetic acid and propionic acid.

<span class="mw-page-title-main">Interleukin 31</span>

Interleukin-31 (IL-31) is a protein that in humans is encoded by the IL31 gene that resides on chromosome 12. IL-31 is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. It has also been identified as a major player in a number of chronic inflammatory diseases, including atopic dermatitis.

<span class="mw-page-title-main">Janus kinase 3</span> Mammalian protein found in Homo sapiens

Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the JAK3 gene.

<span class="mw-page-title-main">Janus kinase 1</span>

JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family. It is also important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptors. Jak1 plays a critical role in initiating responses to multiple major cytokine receptor families. Loss of Jak1 is lethal in neonatal mice, possibly due to difficulties suckling. Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

Senile pruritus is one of the most common conditions in the elderly or people over 65 years of age with an emerging itch that may be accompanied with changes in temperature and textural characteristics. In the elderly, xerosis, is the most common cause for an itch due to the degradation of the skin barrier over time. However, the cause of senile pruritus is not clearly known. Diagnosis is based on an elimination criteria during a full body examination that can be done by either a dermatologist or non-dermatologist physician.

<span class="mw-page-title-main">Tofacitinib</span> Medication

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Janus kinase 3 inhibitor</span>

Janus kinase 3 inhibitors, also called JAK3 inhibitors, are a new class of immunomodulatory agents that inhibit Janus kinase 3. They are used for the treatment of autoimmune diseases. The Janus kinases are a family of four nonreceptor tyrosine-protein kinases, JAK1, JAK2, JAK3, and TYK2. They signal via the JAK/STAT pathway, which is important in regulating the immune system. Expression of JAK3 is largely restricted to lymphocytes, while the others are ubiquitously expressed, so selective targeting of JAK3 over the other JAK isozymes is attractive as a possible treatment of autoimmune diseases.

Lokivetmab, trade name Cytopoint, is a monoclonal antibody used to treat atopic dermatitis in dogs. It acts against interleukin 31 (IL-31), which is a cytokine involved in causing itchiness (pruritus). Lokivetmab is administered by subcutaneous injection; each dose is effective for four to eight weeks.

<span class="mw-page-title-main">Abrocitinib</span> Chemical compound

Abrocitinib, sold under the brand name Cibinqo, is a medication used for the treatment of atopic dermatitis (eczema). It is a Janus kinase inhibitor and it was developed by Pfizer. It is taken by mouth.

Brian S. Kim is the Sol and Clara Kest Professor, Vice Chair of Research, and Site Chair of Mount Sinai West and Morningside in the Kimberly and Eric J. Waldman Department of Dermatology at Icahn School of Medicine at Mount Sinai. He is also Director of the Mark Lebwohl Center for Neuroinflammation and Sensation.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Apoquel- oclacitinib maleate tablet, coated". DailyMed. 28 July 2021. Retrieved 19 February 2024.
  2. 1 2 "Prolevare EPAR". European Medicines Agency (EMA). 17 February 2023. Retrieved 19 February 2024.
  3. 1 2 "FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs" (Press release). Zoetis. 16 May 2013. Archived from the original on 23 February 2017. Retrieved 23 February 2017.
  4. 1 2 Gonzales AJ, Bowman JW, Fici GJ, Zhang M, Mann DW, Mitton-Fry M (August 2014). "Oclacitinib (Apoquel) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy". Journal of Veterinary Pharmacology and Therapeutics. 37 (4): 317–324. doi:10.1111/jvp.12101. PMC   4265276 . PMID   24495176.
  5. ↑ "Prolevare Film-coated tablet". European Medicines Agency (EMA). 23 April 2023. Retrieved 19 February 2024.
  6. 1 2 Cowan A, Yosipovitch G (2015). Pharmacology of Itch. Springer. pp. 363–364. ISBN   978-3-662-44605-8.
  7. 1 2 3 Hnilica KA, Patterson AP (2016). Small Animal Dermatology - E-Book: A Color Atlas and Therapeutic Guide. Elsevier Health Sciences. p. 190. ISBN   978-0-323-39067-5.
  8. ↑ Cote E (2014). Clinical Veterinary Advisor - E-Book: Dogs and Cats. Elsevier Health Sciences. p. 1765. ISBN   978-0-323-24074-1.
  9. 1 2 3 4 5 6 7 8 Falk E, Ferrer L (December 2015). "Oclacitinib" (PDF). Clinician's Brief. Archived from the original (PDF) on 2017-05-17. Retrieved 2018-02-28.
  10. ↑ Moriello K. "Canine Atopic Dermatitis". Merck Veterinary Manual. Retrieved 27 February 2018.
  11. 1 2 3 Papich MG (2015). Saunders Handbook of Veterinary Drugs: Small and Large Animal. Elsevier Health Sciences. p. 574. ISBN   978-0-323-24485-5.
  12. 1 2 3 4 5 6 Riviere JE, Papich MG (2017). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. pp. 2955–2966. ISBN   978-1-118-85588-1.
  13. 1 2 3 Saridomichelakis MN, Olivry T (January 2016). "An update on the treatment of canine atopic dermatitis". Veterinary Journal. 207: 29–37. doi:10.1016/j.tvjl.2015.09.016. PMID   26586215. S2CID   9511235.
  14. 1 2 3 4 Barnette C (2017). "Oclacitinib". VCA. LifeLearn. Retrieved 27 February 2018.
  15. 1 2 Layne EA, Moriello KA (1 April 2015). "What's new with an old problem: Drug options for treating the itch of canine allergy". dvm360. Archived from the original on 4 March 2018. Retrieved 27 February 2018.
  16. 1 2 "Apoquel, INN-oclacitinib maleate" (PDF). European Medicines Agency. Retrieved 27 February 2018.
  17. ↑ Cosgrove SB, Wren JA, Cleaver DM, Walsh KF, Follis SI, King VI, et al. (December 2013). "A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel) in client-owned dogs with atopic dermatitis". Veterinary Dermatology. 24 (6): 587–97, e141-2. doi:10.1111/vde.12088. PMC   4286885 . PMID   24581322.
  18. 1 2 3 Damsky W, King BA (April 2017). "JAK inhibitors in dermatology: The promise of a new drug class" (PDF). Journal of the American Academy of Dermatology. 76 (4): 736–744. doi:10.1016/j.jaad.2016.12.005. PMC   6035868 . PMID   28139263. Archived from the original (PDF) on 2018-03-04. Retrieved 2018-03-04.
  19. ↑ Olivry T, Mayhew D, Paps JS, Linder KE, Peredo C, Rajpal D, et al. (October 2016). "Early Activation of Th2/Th22 Inflammatory and Pruritogenic Pathways in Acute Canine Atopic Dermatitis Skin Lesions". The Journal of Investigative Dermatology. 136 (10): 1961–1969. doi: 10.1016/j.jid.2016.05.117 . PMID   27342734.
  20. 1 2 Fukuyama T, Ganchingco JR, Bäumer W (January 2017). "Demonstration of rebound phenomenon following abrupt withdrawal of the JAK1 inhibitor oclacitinib". European Journal of Pharmacology. 794: 20–26. doi:10.1016/j.ejphar.2016.11.020. PMID   27847179. S2CID   41919568.
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