Safety of the Selective JAK1 Inhibitor Oclacitinib in Dogs

Abstract

Apoquel(oclacitinib maleate) as a film-coated tablet, a selective Janus kinase (JAK)1 inhibitor, was approved by the United States Food and Drug Administration (FDA) in 2013 for the control of pruritus associated with allergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age. The goal of this review is to describe the safety of oclacitinib in dogs based on data from investigational laboratory and field studies, independent directed studies, and an extensive postmarketing pharmacovigilance (PV) surveillance program. The safety of oclacitinib has been extensively evaluated in investigational and independent studies. In the oclacitinib postapproval PV surveillance, the types and rank order of frequency of reported adverse events were similar to the premarketing field studies, with diarrhea, anorexia, and lethargy being the most frequently reported adverse events. In the postmarketing PV continuous monitoring, adverse events for patients receiving oclacitinib are rarely reported and the individual clinical signs within the PV adverse event reports were considered "very rare" in frequency. An age- and breed- matched retrospective cohort study in dogs with allergic dermatitis showed no significant difference in incidence of neoplasia between dogs treated with oclacitinib and dogs treated with other systemic therapies. The extensive investigational and PV experience with oclacitinib shows that long-term or lifelong use per label instructions has a positive benefit-risk profile and is not associated with any cumulative safety risk.

Keywords: JAK1 selective inhibitor; adverse events; allergic dermatitis; atopic dermatitis; dogs; oclacitinib; pharmacovigilance; safety.

FIGURE 1

Schematic representation of cytokine cell surface receptor families and associated receptor complexes that utilize intracellular JAK enzymes for signaling. The functional responses to receptor complex activation are listed. Many of the cytokines involved in allergy, inflammation, and pruritus bind to receptor complexes that utilize JAK1 as one of the obligate JAK partners. Oclacitinib was shown to inhibit JAK1‐dependent cytokines involved in allergy, inflammation, and pruritus (IL‐2, IL‐4, IL‐6, IL‐13, and IL‐31) (Hu et al. ; Rusinol and Puig ; Gonzales et al. , ; Marsella et al. 2012). EPO, Erythropoietin; G‐CSF, Granulocyte colony‐stimulating factor; GM‐CSF, Granulocyte‐macrophage colony‐stimulating factor; gp, Glycoprotein; IFN, Interferon; IFNR, Interferon receptor; IL, Interleukin; JAK, Janus kinase; NK, Natural killer cell; R, Receptor; Th, T helper cell; Tyk, Tyrosine kinase. EPO: Erythropoietin; G‐CSF: Granulocyte colony‐stimulating factor; GM‐CSF: Granulocyte‐macrophage colony‐stimulating factor; gp: Glycoprotein; IFN: Interferon; IFNR: Interferon receptor; IL: Interleukin; JAK: Janus kinase; NK: Natural killer cell; R: Receptor; Th: T helper cell; Tyk: Tyrosine kinase.

FIGURE 2

Relationship between oclacitinib plasma concentration in dogs and inhibition of cytokine function. Oclacitinib (oral tablet) was administered once‐daily (SID) or twice‐daily (BID). JAK1‐dependent cytokine IC_50s (plasma concentration required to inhibit cytokine activity by 50%) are shown in blue and JAK2‐dependent cytokine IC_50s are shown in red. Oclacitinib at the recommended dose and regimen generates plasma concentrations that preferentially inhibit pruritogenic and pro‐inflammatory JAK1‐dependent cytokines while not inhibiting JAK2‐dependent cytokines involved in hematopoiesis and immune function (Marsella et al. 2023). BID, Twice (two times) a day; EPO, Erythropoietin; GM‐CSF, Granulocyte macrophage colony‐stimulating factor; IC₅₀ , Plasma concentration required to inhibit cytokine activity by 50%; IL, Interleukin; JAK, Janus kinase; SID, Once a day.