Oclacitinib

Oclacitinib (brand name Apoquel) 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][2] Chemically, it is a synthetic cyclohexylamino pyrrolopyrimidine janus kinase inhibitor that is relatively selective for JAK1.[3] It inhibits signal transduction when the JAK is activated and thus helps downregulate expression of inflammatory cytokines. While oclacitinib is effective, its long-term safety is currently unknown.

Oclacitinib
Clinical data
Trade namesApoquel
Other namesPF-03394197
AHFS/Drugs.comVeterinary Use
Routes of
administration		By mouth (tablets)
Drug classJAK inhibitor
ATCvet code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability89%
Protein binding66.3–69.7%
MetabolismLiver
Elimination half-life3.1–5.2 hours[1]
ExcretionMostly liver
Identifiers
IUPAC name
  • 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
FormulaC15H23N5O2S
Molar mass337.44 g·mol−1
3D model (JSmol)
SMILES
  • CNS(=O)(=O)C[C@@H]1CC[C@H](CC1)N(C)c2[nH]cnc3nccc23
InChI
  • 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 was approved by the FDA in 2013.[2]

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.[4][5] It is considered to be highly effective in dogs, and has been established as safe for at least short-term use.[6][7][8] 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.[9] It has been found to have a faster onset and cause less gastrointestinal issues than cyclosporine.[7][10]

While safe in the short term, oclacitinib's long-term safety is unknown.[7][11] While some say it is best only for acute flares of itchiness, others claim that it is also useful in chronic atopic dermatitis.[5][11]

There is some off-label use of oclacitinib in treating asthma and allergic dermatitis in cats, but the exact efficacy has not been established.[9][5]

Contraindications

Oclacitinib is not labeled for use in dogs younger than one due to reports of it causing demodicosis.[10] 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;[12] because it is an immune system suppressant, it should not be used in dogs with serious infections.[7]

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.[7]

Side Effects

Oclacitinib lacks the side effects that most JAK inhibitors have in humans; instead, side effects are infrequent, mild, and mostly self-limiting.[10][11][13] 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.[7][12] New cutaneous or subcutaneous lumps, such as papillomas, can appear,[7][14] and dogs face an increased susceptibility to infections such as demodicosis.[1][12] 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][14][15]

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.[7][12]

Oclacitinib is more likely to cause side effects if given twice a day than if given once a day.[9] Some dogs transitioning from twice-a-day to once-a-day dosing have gotten a temporary increase in itchiness.[7]

Pharmacodynamics

Mechanism of Action

Oclacitinib is not a corticosteroid or antihistamine, but rather modulates the production of signal molecules called cytokines in some cells.[10] 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.[16]

Oclacitinib inhibits signal JAK family members (JAK1, JAK2, JAK3, and tyrosine kinase 2), most effectively JAK1, while not significantly inhibiting non-JAK kinases.[3][16]

ReceptorMean IC50 (nM)
JAK110
JAK218
JAK399
TYK284

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][9][10] (TSLP, another pruritogenic cytokine that uses JAKs, has also been found to be inhibited).[17][18] 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.[13] Suppression of IL-4 and IL-13 causes a decrease of Th2-cell differentiation, which plays a role in atopic dermatitis.[16] Oclacitinib's relatively little effect on JAK2 prevent it from suppressing hematopoiesis or the innate immune response.[4][10]

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.[18]

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 renal and biliary clearance as well.[1]

References
  1. "Apoquel (oclacitinib maleate tablet) Full Prescribing Information" (PDF). Zoetis Inc. Kalamazoo, MI 49007. Retrieved 23 February 2017.
  2. "FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs". Zoetis. 16 May 2013. Retrieved 23 February 2017.
  3. 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): 317–24. doi:10.1111/jvp.12101. PMC 4265276. PMID 24495176.
  4. Cowan A, Yosipovitch G (2015). Pharmacology of Itch. Springer. pp. 363–364. ISBN 978-3-662-44605-8.
  5. 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.
  6. Cote E (2014). Clinical Veterinary Advisor - E-Book: Dogs and Cats. Elsevier Health Sciences. p. 1765. ISBN 978-0-323-24074-1.
  7. Falk E, Ferrer L (December 2015). "Oclacitinib" (PDF). Clinician's Brief.
  8. Moriello K. "Canine Atopic Dermatitis". Merck Veterinary Manual. Retrieved 27 February 2018.
  9. Papich MG (2015). Saunders Handbook of Veterinary Drugs: Small and Large Animal. Elsevier Health Sciences. p. 574. ISBN 978-0-323-24485-5.
  10. Riviere JE, Papich MG (2017). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. pp. 2955–2966. ISBN 978-1-118-85588-1.
  11. 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.
  12. Barnette C (2017). "Oclacitinib". VCA. LifeLearn. Retrieved 27 February 2018.
  13. Layne EA, Moriello KA (1 April 2015). "What's new with an old problem: Drug options for treating the itch of canine allergy". dvm360. Retrieved 27 February 2018.
  14. "Apoquel, INN-oclacitinib maleate" (PDF). European Medicines Agency. Retrieved 27 February 2018. {{cite journal}}: Cite journal requires |journal= (help)
  15. 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.
  16. 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.
  17. 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.
  18. 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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