Efficacy of oclacitinib for the control of feline atopic skin syndrome: correlating plasma concentrations with clinical response

Abstract

Objectives

The aim of this study was to assess the efficacy of a new therapeutic regimen of oclacitinib for the control of feline atopic skin syndrome (FASS) and to correlate plasma levels of this drug with clinical effects.

Methods

Twenty-eight client-owned cats with a clinical diagnosis of FASS were recruited. Oclacitinib was administered at 1 mg/kg q12h for 2 weeks and then at 1 mg/kg q24h for a further 2 weeks. At the study outset (D0), and 7 (D7) and 28 (D28) days after starting treatment, clinical lesions were assessed using a validated scoring system (SCORing Feline Allergic Dermatitis [SCORFAD]) and pruritus was graded via an adapted visual analogue scale (PVAS). At the same time points, plasma oclacitinib levels and haematological variables were measured.

Results

Among 18 cats completing the study, PVAS and SCORFAD improved by ⩾50% in 61% and 88% of animals, respectively. Mean PVAS decreased significantly between D0 and D7 and between D0 and D28 (both P <0.001) but not between D7 and D28. Likewise, mean SCORFAD values decreased significantly between D0 and D7 and between D0 and D28 (both P <0.001) but not between D7 and D28. On D7 and D28, plasma oclacitinib concentrations varied widely from 0 to 1443.2 ng/ml and from from 0 to 1177.7 ng/ml, respectively. Oclacitinib concentrations showed no correlation with clinical effects (SCORFAD and PVAS).

Conclusions and relevance

Oclacitinib emerged as being safe and effective to control clinical signs of FASS. A mean dose of 1 mg/kg, even without extending twice-daily treatment beyond the first 2 weeks, could be a suitable therapeutic regimen. Plasma drug levels did not seem useful to predict clinical response during treatment.

Keywords

Atopic syndrome allergy oclacitinib atopic dermatitis dermatology

Introduction

Feline atopic skin syndrome (FASS) is an inflammatory skin disease, triggered by an abnormal complex immunological reaction against environmental allergens, that affects some 12–32% of feline dermatological patients.^1–5 Clinically, FASS is characterised by pruritus and at least one of the classic dermatological patterns: head and neck pruritus and excoriations; eosinophilic dermatitis; auto-induced alopecia; and miliary dermatitis.⁶

Effective control of clinical signs is desirable as FASS reduces the quality of life of both the cat and its owner.^7,8 An aetiopathogenic approach (whereby contact with the allergen is avoided) or specific allergen immunotherapy are often not possible,^9–11 because allergy tests are not performed or, even in doing the test, the obtained result does not allow for specific immunotherapy. Anti-inflammatory/immunosuppressive drugs such as prednisolone or ciclosporin are then needed.¹² However, this option carries risks and must be avoided in patients with certain concomitant diseases.^13,14

In the search for safer therapeutic options, Janus kinase (JAK) inhibitors have recently sparked the interest of clinicians and researchers. These drugs interfere with the intracellular JAK-STAT (signal transducer and activator of transcription) signalling pathway exerting a wide range of anti-inflammatory and immunosuppressive effects. In human medicine, JAK inhibitors have been used to control malignant, myeloproliferative and allergic diseases, usually with associated mild-to-moderate adverse effects.^15,16

Oclacitinib (Apoquel; Zoetis) is a JAK inhibitor registered for the control of pruritus and lesions associated with allergic dermatitis in dogs,^17,18 although it has also proven useful for other canine immune-mediated diseases.^19–21 In controlled clinical studies in dogs, oclacitinib has shown a profound antipruritic effect with only a few described mild or moderate self-limiting adverse effects.^22,23

In cats, oclacitinib has been used off-label for the control of both allergic and non-allergic diseases.^24–30 Success rates for controlling feline hypersensitivity dermatitis have been variable at around 40% and 67%.^28–30 This, along with the good tolerance and only mild and self-limiting adverse effects shown, makes oclacitinib a feasible therapeutic option in cats.¹² However, standardised doses and dosage regimens have not yet been established.

The highly variable pharmacokinetics of oclacitinib observed in the cat could explain the clinical response observed in this species.³¹ To date, the scientific literature lacks reports of studies examining the relationship between plasma levels of this drug and clinical outcome able to explain the lack of response produced in some cats (33–60%).^28–30

The objectives of the present study were: (1) to assess the efficacy of a new therapeutic regimen of oclacitinib used to treat cats with FASS; and (2) to address the relationship between clinical response and plasma oclacitinib concentrations.

Materials and methods

Study design and cat population

This was a prospective, multicentric, non-controlled study carried out by veterinarians with expertise in feline dermatology. Twenty-eight cats of any breed and of both sexes (intact or neutered) that were older than 12 months were initially recruited. All the cats had a sound diagnosis of FASS based on criteria described in the literature.⁶ Briefly, they all had pruritus and showed at least one of the classic lesion patterns: head and neck excoriations; eosinophilic dermatitis; self-inflicted alopecia; and/or miliary dermatitis. Over a period of at least 3 months before the study start, the animals were checked and treated, if necessary, for fleas. Allergic food reactions were ruled out through dietary exclusion based on commercial hydrolysed diets given over at least 8 weeks. Bacterial and fungal infections were also controlled through cytological examinations, Wood’s lamp examination, microscopic examination of plucked hairs and, if necessary, fungal culture.

Exclusion criteria were concomitant diseases, bloodwork abnormalities or animals testing serologically positive for feline immunodeficiency or leukaemia viruses. We also excluded cats that had been treated with one or more of the following compounds: topical glucocorticoids or oral glucocorticoids (in the previous 2 weeks); injectable glucocorticoids (in the previous 8 weeks); oral antihistamines (in the previous week); and ciclosporin or oclacitinib (in the previous 4 weeks). Oral and/or topical antiparasite drugs were allowed.

Oclacitinib treatment

Cats enrolled were given oclacitinib at 1 mg/kg q12h PO for 2 weeks, and then 1 mg/kg q24 h PO for a further 2 weeks. The dose received was estimated based on the weight of the animal and the commercial oclacitinib formulation (3.6 mg, 5.4 mg and 16 mg).

Clinical assessment

At the time points baseline (D0, before treatment), and seven (D7) and 28 (D28) days after starting treatment, participants underwent a dermatological examination. Lesions in 11 established anatomical regions were assessed for severity and extent using a validated scale (SCORing Feline Allergic Dermatitis [SCORFAD]).³² Each lesion was graded on a scale of 0 to 4. At the established time points, owners assessed the level of pruritus using a visual analogue scale ranging from 0 to 10 adapted for use in cats (Pruritus Visual Analogue Scale [PVAS]).³³ For inclusion of a patient, the minimum baseline scores required were 4 in SCORFAD and 7 in PVAS.

Analytical assessment

On the pre-established days (D0, D7 and D28), blood samples were obtained from the jugular or cephalic veins and collected into heparin- and EDTA-coated tubes 1 h after treatment. Plasma was separated and frozen at 20°C within 30 mins of blood collection.

Plasma oclacitinib levels

Oclacitinib was determined in plasma using the high-performance liquid chromatrography (HPLC) method described by Collard et al (2013),³⁴ with some modification.³¹ Briefly, a 50 µl volume of each sample was transferred to a well of a 96-well plate. To all samples, 200 µl of an internal standard M + 4 stable label solution (98.9% purity [Pfizer]) ([internal standard], 10 ng/ml) in acetonitrile was added. The plate was sealed, vortexed and then centrifuged at approximately 100 g for 10 mins to precipitate the proteins. Next, a 20 µl aliquot of each sample was transferred to each well of a clean 96-well plate, diluted with 180 µl 0.1% ammonium hydroxide, sealed and gently mixed. The plate was then placed in the autosampler for liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. A 10 µl volume of each prepared sample was injected into a 5 ml Zorbax Extend C18 50 9 2-mm HPLC column and eluted at 0.300 ml/min using a gradient. The HPLC mobile phases were A (0.1% ammonium hydroxide in water [pH 10.7] and B (0.1% ammonium hydroxide in acetonitrile). Oclacitinib was detected using a Sciex API 4000 mass spectrometer (MDS Sciex). Established limits were detection 0.15 ng/ml and quantification 1 ng/ml. Linearity was observed from 1 to 1000 ng/ml.

Biochemistry and haematological assessment

At each time point, creatinine and alanine transaminase (ALT) levels were determined and a complete blood cell count was performed in house with analysers from Catalyst and Procyte (IDEXX).

Adverse events and withdrawal

Reasons for withdrawal were recorded along with adverse effects observed during treatment, regardless of whether or not they were related to oclacitinib.

Statistical analysis

SCORFAD and PVAS results were expressed as medians, ranges and interquartile ranges (IQRs). For the PVAS data, ANOVA and the Tukey test were used to compare medians and identify differences between pairs, respectively. For the SCORFAD data, ANOVA–Welch and Games–Howell tests were used for the same purpose. All statistical tests were performed using the software package MinitabTM v19.2020.1.0. Significance was set at P <0.05.

Results

Cat population

The 28 cats initially enrolled were 14 males and 14 females, aged 1–13 years and weighing 1.5–8.4 kg. Breeds were domestic shorthair (n = 27) and Maine Coon (n = 1).

Withdrawal

Ten of the 28 cats enrolled were withdrawn from the study at different times. Five cats dropped out because of lack of owner compliance owing to difficulties in oral administration of the tablets; two cats owing to vomiting after treatment administration; two cats because the caregivers considered there to be a lack of treatment efficacy; and the last cat dropped out because of the development of anaemia.

Of these 10 cats, four dropped out during the first week of the study, and the remaining six cats were withdrawn at different times between D7 and D28.

Oclacitinib treatment

The mean doses of oclacitinib used were 0.96 mg/kg q12 h (range 0.84–1.11) in the first 2 weeks, and 0.96 mg/kg q24 h in the second 2 weeks.

Clinical assessment

The four cats withdrawn before D7 were excluded from the statistical analysis. The data compared were those recorded at D0 and D7 in 24 cats and those recorded at D0, D7 and D28 in the 18 cats that completed the whole study. As the result of an appropriate analytical method for each case, variances were equal among PVAS scores but not among SCORFAD values.

When the 18 cats finishing the study were considered, PVAS values were 8 (range 7–9; IQR 7–9), 3.5 (range 1–8; IQR 1–5) and 2.5 (range 0–7; IQR 0–5) on days 0, 7 and 28, respectively. Tukey’s test revealed significant differences between D0 and D7 (P <0.001) and between D0 and D28 (P <0.001) but not between D7 and D28 (Figure 1). From D0 to D7 (n = 24), PVAS scores varied significantly (P <0.001) (8 [range 7–10; IQR 8–9] vs 3 [range 1–9; IQR 2–5]). In these 18 cats, SCORFAD values were 12.5 (range 4–26; IQR 7.7–16.2), 5.0 (range 1–19; IQR 2–8) and 1 (range 0–16, IQR 0–5.2) at D0, D7 and D28, respectively. The Games–Howell test identified significant differences between D0 and D7 (P <0.001), D0 and D28 (P <0.001) but not between D7 and D28 (Figure 2). From D0 to D7 (n = 24), SCORFAD scores were found to differ significantly (P <0.001) (12.5 [range 4–26; IQR 8–16] vs 5 [range 1–23; IQR 2.2–8]).

Figure 1

Pruritus visual analogue scale (PVAS) scores awarded by the cat owners on day 0 (D0, before treatment), and 7 (D7) and 28 days (D28) post-treatment onset (n = 18). Scores are provided as medians (range; interquartile range). The mean is indicated by the ‘X’. Significant differences (***P <0.001) were observed between baseline scores (D0) and those obtained at D7 and D28

Figure 2

SCORing Feline Allergic Dermatitis (SCORFAD) scores awarded by the cat owners on day 0 (D0, before treatment), and at days 7 (D7) and 28 (D28) post-treatment onset (n = 18). Scores are provided as medians (range; interquartile range). ‘X’ indicates the mean and the dots outliers. Significant differences (***P <0.001) were observed between baseline scores (D0) and those obtained at D7 and D28

Of the 18 cats that completed the course of treatment, improvements in PVAS and SCORFAD ⩾50% were observed in 11 (61%) and 16 (89%) cats, respectively.

Plasma oclacitinib levels

Plasma oclacitinib levels measured on D7 (n = 24) and D28 (n = 18) varied widely: from 0 to 1443.2 ng/ml and from 0 to 1177.7 ng/ml, respectively. Hence, changes in SCORFAD and PVAS could not be correlated with oclacitinib levels (Figure 3).

Figure 3

Plasma oclacitinib concentrations recorded on days 7 (D7) and 28 (D28) post-treatment onset. Every dot represents one cat. Clinical improvement and SCORing Feline Allergic Dermatitis (SCORFAD) and Pruritus Visual Analogue Scale (PVAS) scores are represented as: green >75%; yellow 50–75%; red <50%

Biochemistry and blood work

Haematocrit only decreased in one cat in the first week, from 34% recorded at baseline to 19%. After stopping treatment, this value returned to 29%. Leucocyte levels remained stable throughout the study in all animals but one, in which levels fell from 5.5 K/µl (D0) to 2.3 K/µl (D7), yet returned to 5.03 K/µl on D28 without specific treatment.

Biochemistry tests revealed an elevated plasma ALT concentration in two animals at D28 (288 and 473 U/l) with no associated clinical signs. Creatinine levels were stable during the study.

Adverse events

Besides the haematocrit changes produced in one cat, which prompted its withdrawal from the study, vomiting after treatment administration was observed in two cats, which resolved after the discontinuation of oclacitinib.

Discussion

The mean dose of 1 mg/kg of oclacitinib used during the study was based on previous work, in which better clinical effects were observed using higher doses than recommended in dogs,²⁹ and on reported pharmaco-kinetic data, in which higher doses seemed to be necessary in cats.³¹ Furthermore, oclacitinib seemed mostly well tolerated in cats, even when used in the long term and at high doses.^35,36

In the present study, patients received a dose of 1 mg/kg q12h during the first 2 weeks, and then the same dose of 1 mg/kg q24h for the remaining 2 weeks of the study, in an attempt to achieve an easier once-daily therapeutic regimen for both the patient and the caregiver.

With this therapeutic regimen, pruritus and lesion severity decreased significantly from the first week; this improvement was maintained over the remaining weeks of treatment (Figures 1 and 2). In fact, the owners reported the resolution of pruritus after just the first or second days of treatment (data not shown). These observations are similar to those reported in dogs, where oclacitinib has been proven to be a good option for the pharmacological control of allergic pruritus.^18,22,23

As expected, the success rates were better than those obtained with lower doses of oclacitinib (0.4–0.6 mg/kg) to control the clinical signs of FASS in cats. Nevertheless, for a similar mean dose used, our outcomes were still better than those described by Noli et al²⁹ in that greater decreases were observed in both SCORFAD (76% vs 61%) and PVAS (66% vs 54%) scores, despite a lower frequency of administration in the present study (Table 1).

Table 1

Comparison of oclacitinib doses, therapeutic regimens and results of the present and other studies

Reference and study design	n	Mean dose (mg/kg)	Regimen		Improvement
Reference and study design	n	Mean dose (mg/kg)	Regimen		Percentage of cats improving by ⩾50%	Improvement in SCORFAD and PVAS (%)
Fernandes et al,³⁵ case report	1	1	1 mg/kg q24h for 2 weeks	SCORFAD	100	NR
Fernandes et al,³⁵ case report			1 mg/kg q12h for 300 days	PVAS	100	NR
Ortalda et al,²⁸ case series	12	0.47	0.47 mg/kg q12h for 2 weeks	SCORFAD	42	22
Ortalda et al,²⁸ case series			0.47 mg/kg q24h for 2 weeks	PVAS	42	17
Pandolfi et al,³⁰ case series	15	0.65	0.65 mg/kg q12h for 2 weeks	SCORFAD	66	NR
Pandolfi et al,³⁰ case series			0.65 mg/kg q24h for 2 weeks	PVAS	66	NR
Noli et al,²⁹ RCT	20	0.9	0.9 mg/kg q12h for 4 weeks	SCORFAD	60	61
Noli et al,²⁹ RCT				PVAS	70	54
Present study, case series	18	0.96	0.96 mg/kg q12h for 2 weeks	SCORFAD	88	76
Present study, case series			0.96 mg/kg q24h for 2 weeks	PVAS	61	66

SCORFAD = SCORing Feline Allergic Dermatitis; PVAS = Pruritus Visual Analogue Scale; RCT = randomised controlled trial; NR = not reported

Based on our results, it does not seem necessary to continue treatment q12h beyond the first 2 weeks, thus reducing costs, possible adverse effects and improving patient management. Although only 3/28 cats dropped out because of difficulties with the oral administration, indicating that oclacitinib was overall well tolerated, a once daily basis is more desirable for both owners and patients.⁸

We also tried to correlate plasma levels of oclacitinib with clinical outcome as this could help explain why some cats do not respond to therapy, even at higher doses, allowing for individualised dosing and follow-up. Unfortunately, we detected no relationship between these two factors in our participants. In effect, some animals with low blood oclacitinib concentrations showed a remarkable clinical response, while others with high concentrations at the time of measurement showed only mild clinical improvement (Figure 3).

The absorption and elimination of oclacitinib is faster in cats than dogs.³¹ This means that in cats the exact timing of blood sampling could be especially important, even within a few minutes. We collected blood 1 h post-drug administration, on the basis that, in a pharmacokinetic study, the C_max of oral oclacitinib in the cat was detected at 0.58 h (±0.08).³¹ As we worked with client-owned cats, some variation or inaccuracy in timing would be expected as owners were instructed to administer the drug at home and then take the cat to the hospital for oclacitinib determination. Other pharmacokinetic and pharmacodynamic factors could also have contributed to the lack of correlation detected between plasma concentrations of the drug and its pharmacological activity, such as inter-individual variation in occupied drug receptors.

To assess the safety of oclacitinib, clinical signs and analytical changes were recorded during the study. While gastrointestinal events have been the adverse effects most often related to oclacitinib,¹² only two cats dropped out the study because of vomiting, which was likely attributable to the treatment.

When we monitored complete blood counts, a drop in haematocrit after 1 week of treatment was detected in only one cat. In the following week, this value returned to normal after stopping therapy. In human medicine, cytopenia has been well recognised during JAK inhibitor treatment, mainly in those exerting a greater influence on JAK2,¹⁶ involved in haematopoiesis. As oclacitinib shows around two-fold selectivity towards JAK1 vs JAK2,¹⁷ we speculated that this was inherently different in this particular cat.

As seen in other studies,¹² ALT levels increased during treatment in two of our patients but with no associated clinical signs. No hepatic ultrasound and/or biopsies were performed because ALT values returned to normal after stopping the treatment.

Conclusions

The results of this study indicate that oclacitinib is an effective and mostly safe and well tolerated therapeutic option for controlling the clinical signs of FASS in cats. A mean dose of 1 mg/kg was found to return results as good as those observed in dogs, even when a twice-daily induction dose was given over only 2 weeks.

Plasma levels of oclacitinib could not be related to the clinical response to treatment. While this finding needs to be confirmed in a larger population of cats, further work is needed to examine why oclacitinib is not effective in some animals. It is appropriate to highlight that the use of oclacitinib in cats has not yet been approved and long-term safety studies should also be carried out including a larger population of cats. Until more information on the safety of oclacitinib use in cats is available, it is probably appropriate to perform routine blood tests during the first 2 weeks of treatment and periodically thereafter if treatment is continued.

Footnotes

Accepted: 6 September 2021

Conflict of interest

Isaac Carrasco has received unrelated payment from Zoetis, Leti-Pharma, MSD Animal-Health, Dechra and Vetnova for lecturing and/or consulting. Lluis Ferrer has also received unrelated payment from Zoetis, Elanco Animal Health, CEVA Animal Health, Leti-Pharma and Affinity Petcare for lecturing and/or consulting. The other authors declare no conflicts of interest.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethics approval

The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS. Although not required, where ethical approval was still obtained, it is stated in the manuscript.

Informed consent

Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedure(s) undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required

ORCID iD

Isaac Carrasco

Anna Puigdemont

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