Oclacitinib

Clinical data
Trade names	Apoquel
Synonyms	PF-03394197
AHFS/Drugs.com	Veterinary Use
Routes of administration	By mouth (tablets)
Drug class	JAK inhibitor
ATCvet code	QD11AH90 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	89%
Protein binding	66.3–69.7%
Metabolism	Liver
Elimination half-life	3.1–5.2 hours[1]
Excretion	Mostly liver
Identifiers
IUPAC name N-Methyltrans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclohexylmethanesulfonamide
CAS Number	1208319-26-9
PubChem CID	44631938
ChemSpider	28528036
UNII	99GS5XTB51
KEGG	D10141
ChEMBL	CHEMBL2103874
Chemical and physical data
Formula	C15H23N5O2S
Molar mass	337.44 g·mol−1
3D model (JSmol)	Interactive image
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 (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 was approved by the FDA in 2013.^[2]

Uses[edit]

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 long term in terms of itchiness and dermatitis.^[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[edit]

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).^[12] 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;^[13] 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[edit]

Oclacitinib lacks the side effects that most JAK inhibitors have in humans; instead, side effects are infrequent, mild, and mostly self-limiting.^[10][11][14] 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][13] New cutaneous or subcutaneous lumps, such as papillomas, can appear,^[7][12][15] and dogs face an increased susceptibility to infections such as demodicosis.^[1][12][13] 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][12][15][16]}

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][13]

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[edit]

Mechanism of action[edit]

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.^[17]

Oclacitinib inhibits signal JAK family members (JAK1, JAK2, JAK3, and tyrosine kinase 2), most effectively JAK1, while not significantly inhibiting non-JAK kinases.^[3][17]

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).^[18][19] 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.^[14] Suppression of IL-4 and IL-13 causes a decrease of T_h2-cell differentiation, which plays a role in atopic dermatitis.^[17] 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 than 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.^[19]

Pharmacokinetics[edit]

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.^[12] Oclacitinib is cleared mostly by being metabolized in the liver, though there is some renal and biliary clearance as well.^[1]

References[edit]

External links[edit]

• Official website