Voluntary acceptance and consumption of two oral ciclosporin formulations in dogs: two randomised, controlled studies

Ciclosporin is a lipophilic cyclic polypeptide with powerful immunosuppressive and immunomodulatory properties which was first licensed for the management of canine atopic dermatitis (AD) in 2002 as Atopica® (Novartis Animal Health) and is now approved and available in over 20 countries worldwide.

Ciclosporin at an initial dosage of 5 mg/kg, PO, every 24 hours has been largely demonstrated to be highly effective in the treatment of AD in dogs and remains nowadays one of the most important tools within a multimodal treatment strategy [1]. As a consequence, the International Task Force for Canine Atopic Dermatitis (now the International Committee for Allergic Diseases in Animals [ICADA]) practice guidelines for the treatment of canine AD has specifically been recommending the use of ciclosporin as one of the management tool for chronic AD since 2010. However, the non-palatable capsule formulation of Atopica raises some concerns about compliance in a long-term treatment strategy.

A new oral liquid formulation of ciclosporin (Cyclavance®, Virbac) has recently been approved in Europe, thus offering an alternative method of administration and making it possible to adjust individual dosages with accuracy. It is a 100 mg/ml oral solution indicated in dogs for the treatment of chronic clinical manifestations of AD. After oral administration of ciclosporin at the labeled recommended dose rate of 5 mg/kg bodyweight, peak blood concentrations are achieved within 1–2 h [2]. Being lipophilic, ciclosporin is distributed widely in the body with skin and adipose tissue acting as principal storage sites. The concentration of ciclosprin in skin is up to 10 times higher than that in blood. The high skin concentrations and the relatively long half-life of the drug (average 8.6 h) support once daily dosing in dogs [2,3]. Therefore, Cyclavance®, like Atopica®, could initially be given daily until a satisfactory clinical improvement is seen and then can be given every other day, and eventually in some cases every 3 to 4 days, as a maintenance dose [4].

The liquid form of ciclosporin has been designed to be easier to administer than the capsule form. Our hypothesis was therefore that it would be more acceptable to dogs and reduce the need for forced administration. It was decided to compare, in two separate studies, the dogs’ voluntary acceptance and consumption of both presentations when presented in a bowl mixed with a small amount of food (study 1), and when administered directly into the mouth (study 2).

Canine AD is a chronic disease that requires long-term treatment strategy. Thus, ease of administration, voluntary acceptance and consumption of drugs used for AD management are of primary importance to promote treatment success. To the authors’ knowledge, despite a high number of publications and studies performed on dogs, up to now no study had been specifically designed to investigate the acceptance and the consumption of ciclosporin. The procedures used in the reported studies (appropriate investigator and animal training to test procedures, tests performed at a fixed time every day, use of a cross-over design and of a randomised allocation plan) are derived from those used in the pet food industry in order to reduce bias [6,7]. Furthermore, 20 dogs and at least two days were reported in previous publications to be sufficient when determining palatability differences between any two food samples with sufficient accuracy and efficiency [8]. In the present studies, acceptance tests were run over a period of as long as 14 days. However, some limitations of the reported studies can be pointed out. As for most palatability studies, study 2 was performed with only one dog breed (Beagles) and even if no breed recommendations have been made for assessing both food and drug palatability, the sample used was not representative of the real population of dogs. The environmental conditions were not strictly controlled throughout study 1 and it is not possible to discount the possibility that variations may have affected the result between testing periods. Finally, it has been suggested that acceptance of a product may differ between animals kept under experimental and field conditions and that definitive assessment of palatability should be done in the consumers' home [9]. However, the results of the two studies reported in this paper certainly give clear indications on how Cyclavance® will be accepted by owners’ dogs. Indeed, since the assessment of its full consumption can be considered as a direct measure of its compliance [9], Cyclavance®, either administered with a small amount of food or directly into the dogs’ mouth, should help facilitate long-term administration. In that sense, it is interesting to note that, in study 1, 59 dogs out of 60 had a complete consumption of the 3 doses of Cyclavance® over the 3-day study period (indeed only 1 dog had partial consumption on day 1 and then no consumption on days 2 and 3) whereas no dogs in the Atopica group took the 3 doses (2 dogs took 2 doses). Furthermore, besides the ease of use of an oral syringe, Cyclavance® also enables more accurate dosage.

In an attempt to further facilitate product administration, ciclosporin was administered with a small amount of food in study 1. Knowing that the average food consumption per dog and per day was comprised between 200 and 400 grams during the course of this study, the 30 grams of kibbles given with the products represented about 10% of the dogs’ daily food intake. Moreover, considering that the acceptance tests took place each day 5.5 hours after the dogs’ meal time, it can be assumed that in study 1, the study design is compatible with the recommendation that the products should be given apart from meals. The effect of feeding on ciclosporin oral bioavailibity and efficacy is controversial in the literature. The absolute oral bioavailability of ciclosporin in dogs is low and highly variable. This can be explained by the high molecular weight of the drug, its low water solubility, the effect of the P-glycoprotein efflux pump at the intestinal level, and metabolism by cytochrome P450 3A enzymes located in the small intestinal mucosa and liver [2]. The product labelling for Atopica® and Cyclavance® therefore mention that both products should be administered at least 2 hours apart from feeding rather than at mealtimes. This precaution of use is supported by one study that tested the influence of the feeding status at the time of administration. The administration of ciclosporin to healthy beagles with their daily meal decreased the bioavailability and increased the individual variability of drug absorption [10]. In the same study, pharmacokinetic parameters in fed or fasted dogs receiving ciclosporin as solution or capsule were measured. Cmax tended to be lower after capsule administration and was also decreased by 23% in fed dogs compared with fasted dogs. In five of the 16 dogs which received the drug with food, Cmax and AUC did not reach 50% of the mean values obtained in the fasted dogs [10]. However, clinical response to therapy is a more reliable method of assessing efficacy of ciclosporin than interpretation of ciclosporin blood level. Moroever no correlation was found between clinical improvement and ciclosporin blood concentrations [11]. Indeed, in AD, ciclosporin target cells include Langerhans cells, mast cells, eosinophils and keratinocytes located in the skin. Since the drug concentration in epidermis and dermis is about 10-fold higher than in the blood, drug concentration in the skin may be sufficient to inhibit the activation of these cells involved in the inflammatory process [10]. Furthermore, another study found that administration of ciclosporin with food to dogs treated for AD did not influence the clinical response [12] and clinical experience has shown that efficacy seems unaffected by administration with food [3]. In conclusion, mixing ciclosporin with a small amount of food (i.e. 30 grams as in study 1) for easier administration should have, if any, very limited effects on its bioavailability or, more importantly, on the clinical response when used in canine AD.

Results of previous studies have suggested that ciclosporin is safe in dogs. Most adverse effects are manageable and/or without clinical significance, even over many years of treatment [1]. The most common adverse effects are gastrointestinal tract abnormalities during the first weeks of treatment [13,14]. In a meta-analysis of 672 atopic dogs treated with ciclosporin, gastrointestinal problems were recorded in 45 percent of dogs [15]. Vomiting was reported in 25 to 31 % of dogs and soft stools, diarrhea and/or other problems affected 18 to 20 % of the dogs receiving ciclosporin [15]. Most of the gastrointestinal upsets appear to be mild, require medical intervention only in rare instances [14], rarely require discontinuation of ciclosporin [14], and generally improve spontaneously upon further administration [16]. When drug related, most of these reactions appear to be dose dependent, and they resolve with dose reduction or treatment discontinuation [5]. Suggestions from the literature to reduce the incidence of vomiting and/or diarrhoea are to administer ciclosporin with a small amount of food [11] and/or to start treatment with a low dose (1 to 2 mg/kg every 24 hours) gradually increasing to the therapeutic dose (5 mg/kg every 24 hours) [15]. In study 2 we took advantage of the flexibility permitted by the use of the oral dosing syringe with a liquid formulation and applied this strategy for Cyclavance®. However the number of dogs in this study was not sufficient to answer the question of whether there will be any statistically significant difference between dogs receiving a progressive dosage increase of ciclosporin from 1 to 5 mg/kg over the first five days of dosing compared to those administered 5 mg/kg bodyweight from the onset of treatment. This subject should be further explored in future studies in field conditions using atopic dogs.

Such a progressive onset of treatment is unlikely to have any real impact on treatment efficacy. Usually, even if owners report a significant reduction of pruritus as early as 7–8 days in dogs treated with ciclosporin alone, it requires approximately three to four weeks of therapy at 5 mg/kg once daily for maximal clinical improvement [3,16]. The extent and severity of skin lesions is improved by approximately 50% in the first 4 weeks of treatment with a further improvement of up to 60–80% of the lesions severity obtained in the maintenance phase. The extent of improvement seems to be however more dependent upon treatment duration than the daily dose related to the body weight [10]. Furthermore, in a study where the initial dosage of ciclosporin ranged from 3.3 to 6.6 mg/kg, PO, every 24 hours, it was found that in this dosage range, there was no relationship between dosage and clinical response after 4 weeks [10]. This suggests that in this study, clinical response plateaued at dosages higher than 3.3 mg/kg. On the other hand, in a previous study a dosage of 2.5 mg/kg, PO, every 24 hours for 6 weeks was found to be significantly less effective than a dosage of 5 mg/kg [14]. These data suggest the need to conduct studies to evaluate ciclosporin efficacy in the treatment of canine AD after progressive dosage increase during treatment initiation and to investigate the impact on the frequency of side effects observed during this period.

The liquid formulation of Cyclavance® is easy to administer and enables accurate dosage adjustments. Furthermore, the results of two distinct studies showed that the voluntary prehension, acceptance and consumption of Cyclavance® is significantly better than that of Atopica® when administered either directly into the dog’s mouth or mixed with a small amount of food. In chronic diseases such as canine AD requiring a long-term treatment strategy, these attributes are of primary importance for good patient and owner dosing compliance and thereby therapeutic success.