Transdermal methimazole treatment in cats with hyperthyroidism

Abstract

The objectives of this study were to assess serum thyroxine concentrations and clinical response in hyperthyroid cats to treatment with transdermal methimazole, and to determine if further investigation is indicated.

Clinical and laboratory data from 13 cats with hyperthyroidism were retrospectively evaluated. Methimazole (Tapazole, Eli Lilly) was formulated in a pleuronic lecithin organogel (PLO)-based vehicle and was applied to the inner pinna of the ear at a dosage ranging from 2.5 mg/cat q 24 h to 10.0 mg/cat q 12 h. During the treatment period, cats were re-evaluated at a mean of 4.3 weeks (recheck-1), and again at a mean of 5.4 months (recheck-2).

Clinical improvement was observed, and significant decreases in thyroxine concentrations were measured at recheck-1 (mean: 39.57 nmol/L, SEM: 14.4, SD: 41.2) and recheck-2 (mean: 36.71 nmol/L, SEM: 13.9, SD: 45.56) compared to pretreatment concentrations (mean: 97.5 nmol/L, SEM: 11.42, SD: 39.5). No adverse effects were reported.

Hyperthyroidism is the most common endocrinopathy in feline patients older than 8 years of age (Feldman & Nelson 1996). Feline hyperthyroidism is a multisystemic disorder resulting from an excessive production of thyroxine and tri-iodthyronine by the thyroid glands. The disorder is easily diagnosed and treatment options include surgical and medical interventions. Surgical therapy may not be an option in some cases, especially if concurrent disease is present. Medical management options include drugs that inhibit thyroid hormone synthesis and radioactive iodine therapy.

Medical treatment with thyroid hormonesynthesis inhibitors usually consists of long-term, daily administration of oral formulations. The antithyroid drugs commonly prescribed are methimazole, and carbimazole. Carbimazole is currently not available in the United States (Retsios 2001).

Daily oral administration of methimazole is frequently chosen for the long-term treatment of feline hyperthyroidism and is also frequently administered for several weeks prior to definitive curative therapy (radio-iodine therapy or surgery) in order to unmask subclinical renal disease or to minimise the risks of surgical and anaesthetic complications associated with thyrotoxicosis (Feldman & Nelson 1996; Peterson et al 1988; DiBartola et al 1996).

It is often difficult for pet owners to administer oral medications to cats on a long term basis. The use of a gel containing methimazole for transdermal application provides pet owners with an alternative route of administration that may be better tolerated by these patients and result in better compliance by the owners. Currently, pharmacokinetic data of transdermally applied methimazole is not available for the cat and, to the authors' knowledge, no investigations have been published concerning the efficacy and side effects of this treatment modality.

Our hypothesis was that the administration of methimazole transdermally would lead to significant decreases in serum T4 concentrations in cats with hyperthyroidism. Our objectives were to assess serum thyroxine concentrations before and during treatment with transdermal methimazole in hyperthyroid cats, to investigate the clinical response to this application modus, and to determine if further pharmacokinetic studies are indicated.

Materials and methods

The study population consisted of 13 consecutively identified cats that had been diagnosed with hyperthyroidism and treated with transdermally administered methimazole. The cats were identified through the records of an endocrine diagnostic laboratory. ^a Serum samples had been sent to this laboratory for assessment of thyroxine concentrations by chemiluminescence. ^b Clinical and laboratory data from the cats were retrospectively evaluated by telephone conversations with the veterinarians who managed the cases. The breed distribution included 11 domestic shorthair cats, one Persian and one domestic longhair patient, with a mean and median age of 13.7 and 14 years (range 9–16 years). Six patients were female, including four spayed and two intact cats, and seven patients were neutered males. Hyperthyroidism was diagnosed based on consistent clinical signs and increased total thyroxine, TT4 (12/13), or a combination of a high-normal TT4, increased free thyroxine concentrations (FT4) and consistent clinical signs (1/13). FT4 was estimated using a radioimmunoassay ^c after an equilibrium dialysis step was performed.

Methimazole was formulated in a pleuronic lecithin organogel (PLO)-based vehicle at a concentration of 5 mg Tapazole® ^d /0.1 ml gel. All preparations were formulated and dispensed by the same pharmacy ^e and were to be kept at room temperature. Further details on the preparation of lecithin gels are given elsewhere (Scartazzini & Luisi 1988). Standardised instructions on drug administration were provided to owners, and included the recommendation for protection with gloves while applying the gel to the inner pinna of an ear, rubbing it gently onto the skin after cleaning off a thin film of powder, which might persist from previous application, with a damp paper. No recommendations were made whether to apply the gel to the same ear on every occasion or to change sides. The gel was applied to the ear at a dosage ranging between 2.5 mg/cat q 24 h to 10 mg/cat q 12 h (Table 1). Dosages reflected the clinical choice of the veterinarians who managed the cases. Two cats received other antithyroid drugs prior to the change to transdermal methimazole. Eleven patients were not treated with another antithyroid drug prior to the use of transdermal application. Cats were re-evaluated after a mean and median of 4.3 and 4 weeks, respectively (recheck-1; range: 2.5 to 8 weeks), and again after a mean and median of 5.4 and 6 months, respectively (recheck-2; range: 3 to 7 months). At recheck-1, 10 of 13 cats were evaluated and at recheck-2, eight patients were evaluated. During these consultations occurrence of side effects like nausea, inappetence, lethargy and vomiting, as well as owner compliance were investigated. In addition blood and clinical examinations were undertaken, with particular attention given to the development of local cutaneous reactions. Besides the measurement of thyroid hormones, further laboratory testing available for review by the authors included a complete blood count (5/13), chemistry panel (7/13), and urine analysis (2/13).

Table 1

TT4 concentrations in nmol/l (normal range: 12.3–35.7) and methimazole dose in mg/cat

Cat	Pre treatment	Dosage	Recheck-1	Recheck-2
1	128	5 mg q 12 h	4.6
2	115	5 mg am/2.5 m pm q 12 h	80.6	11.2
3	35.5/FT4: 53	5 mg q 24 h	9.1/16
4	93.7	5 mg am/2.5 mg pm q 12 h		126
5	123	5 mg q 24 h	111
6	126	5 mg q 12 h	21.4	25.7
7	108	5 mg q 12 h		7.4
8	70.3	2.5 mg q 12 h	12.7	25.3
9	150	10 mg q 12h		32.2
10	82.4	5 mg q 12h	23.2
11	112	2.5 q 24–48 h	119	†
12	59	2.5 mg q 12 h	6.4	28.5
13	127.4	5 mg q 12 h	7.7	5.1

Reference range for free T4 (FT4), measured by equilibrium dialysis: 17.2–38.4 pmol/L.

† Euthanasia.

Statistical methods

The thyroxine concentration was considered continuous and was found to follow a normal distribution using the Shapiro–Wilk statistic (null hypothesis of normality could not be rejected at P≤0.05). The thyroxine concentration was evaluated for a change from pre-treatment values using a mixed-effects, general linear model, accounting for the random variance of cat and the repeated measurement on each cat. Where there was a significant fixed effect of time, comparisons were made between recheck-1, recheck-2 and pre-treatment values using the least squares means with type 1 error maintained at 0.05. Thus, where a difference was noted, P≤0.05. PROC UNIVARIATE and PROC MIXED ^f were used.

Results

The cats were diagnosed with hyperthyroidism in eight different veterinary hospitals. Clinical signs reported included weight loss (8/13), inappetence (5/13), mental changes (4/13), vomiting (4/13), diarrhoea (1/13) and polyphagia (1/13). Additional physical examination findings included a palpable nodule in the region of the thyroid gland (6/13), dry haircoat (2/13), a systolic heart murmur (2/13) and tachycardia (2/13). Four cats showed liver enzyme elevations (elevation of ALT 1, 1–3 times of the upper normal range in four cats, AST two times of the upper reference range in one patient).

Two cats received other antithyroid drugs prior to the change to transdermal methimazole. Both underwent a therapeutic change because sustained vomiting occurred following previous medications, which consisted in an oral suspension of methimazole in patient 12 and oral Tapazole®tablets followed by Ipodate in cat 9. Patient 9 was off therapeutics for 2 weeks before transdermal methimazole was initiated, whereas patient 12 underwent an abrupt change in medication. Eleven patients were not treated with another antithyroid drug prior to the use of transdermal methimazole application.

According to the owners, all cats showed clinical improvement following the administration of transdermal methimazole. The veterinarians reported resolution of the following clinical signs: weight loss (5/8), inappetence (4/5), mental changes (3/4), vomiting (3/4), dry hair-coat (2/2). Mild liver enzyme elevations resolved in all but one cat, where fluctuations of ALT and AST occurred in the range of 1–3 times upper normal concentration. Weight gain was documented in four of eight cats in which pre-treatment weight loss had been documented.

Side effects associated with the transdermal delivery of methimazole were not noted in any of the cats. In five patients, the dosage of methimazole was reduced after recheck-1. Total thyroxine concentrations had decreased in nine of 10 cats evaluated at recheck-1, and were within the normal reference range in seven cats. In three cats, there was no or only a mild decrease in thyroxine concentrations. All three were treated with low dosages of topical methimazole (2.5 mg q 24–48 h, 5 mg q 24 h and 3.75 mg q 12 h, respectively), and poor owner compliance was documented in two cases (cat 5 and 11). Cat 11 was euthanised on owner request, the motive for which seemed to be related to difficulties in regularity of drug application.

At recheck-2, normal TT4 concentrations were observed in seven of the eight cats evaluated (Table 1).

There was a significant (P<0.05) decrease in TT4 from pre-treatment concentrations (mean: 97.5 nmol/L, SEM: 11.42, SD: 41.2) to recheck-1 (mean: 39.57 nmol/L, SEM: 14.4, SD: 45.56) and recheck-2 (mean: 36.71 nmol/L, SEM: 13.9, SD: 39.5) but no difference between concentrations at recheck-1 and recheck-2 (Fig 1).

Fig 1

Mean TT4 concentration in nmol/l (normal range: 12.3–35.7). There was a significant (P<0.05) decrease in TT4 from pre-treatment concentrations (mean: 97.5 nmol/l, SEM: 11.42, SD: 41.2) to recheck-1 (mean: 39.57 nmol/l, SEM: 14.4, SD: 45.56) and recheck-2 (mean: 36.71 nmol/l, SEM: 13.9, SD: 39.5) but no difference between concentrations at recheck-1 and recheck-2.

Discussion

Thyroid hormones increase gene transcription in almost all cells and the thyrotoxic state is therefore a multisystemic disease (Becker et al 2000). The synthesis of thyroid hormones is complex and occurs in five main steps: activation and uptake of iodide in the thyroid gland, iodination of thyroglobulin, coupling to thyroid hormones, release of thyroid hormones from thyroglobulin, and conversion from thyroxine to iodothyronine. Thyroid peroxidase, which is inhibited by methimazole, is essential for three of these synthesis steps, catalysing the oxidation of iodide to iodine, iodination of thyrosyl residues in thyroglobulin and the coupling of iodinated thyrosin residues to form thyroxine and iodothyronine.

The efficacy of transdermally delivered methimazole has not previously been reported. The results of this study revealed the association of transdermal application of methimazole and a normalisation of serum T4, because significant reductions in thyroxine were attained, with 10 of 13 cats having serum concentrations in the normal reference range. Although concurrent illness can decrease serum T4, no control group was used and quantitative information beyond T4 was limited in this study, the results may support clinical efficacy. In people the intrathyroidal residence time of methimazole is longer than its serum half life, resulting in longer antithyroid action than would be expected from serum half life, which is only in the range of several hours after oral application in cats (Trepanier et al 1991). If this would prove true for the feline patient, it may make transdermal delivery systems for methimazole less dependant on an exact steady stateabsorption and circadian variations in absorption may have minor impact on the pharmacologic effect.

Three patients in the present study did not show improvements in their serum thyroxine concentrations. A probable reason for this was poor owner compliance, which was documented in two cases (cats 5 and 11). In these patients, drug application was irregular and/or not performed daily (5 mg q 24 h, and 2.5 mg q 24–48 h, respectively). Once daily dosing may lead to therapeutic failure in cases of poor owner compliance because longer time intervals occur between actual drug administrations. In addition, preliminary results of a recently presented study suggested better results were obtained by twice daily dosing regimens of the same total daily dose of oral methimazole in cats with hyperthyroidism compared to a once daily dosing regimen (Hoffman et al 2001). In one patient (cat 4), thyroxine concentrations were increased at recheck-2 but clinical improvement was reported by the owner. This may best be explained by a placebo effect. In addition, the dosage of methimazole might not have been appropriate at the time of recheck-2 (5 mg AM and 2.5 mg PM), which was the first follow-up evaluation of thyroxine after initiation of therapy for this cat. For a more distinct differentiation a prospective study design might be necessary, because dosages of methimazole were notstandardised but reflected the clinical choice of the veterinarians who managed the cases.

Transdermal permeation is a passive process that is primarily prevented by the mildly acidic and hydrophobic stratum corneum of the avascular epidermis. Variations in skin thickness and lipid content of the stratum corneum predict variable skin permeability throughout the body (Goldsmith 1991, Arndt et al 1993). Due to this fact, transdermal application was recommended on the inside of the ear pinna, which has the additional advantage of potentially minimising ingestion during grooming.

Percutaneous absorption is influenced by the characteristics of the vehicle and interactions between the drug and the skin, the vehicle and the skin, and the drug and the vehicle. (Goldsmith 1991, Arndt et al 1993, Bos & Meinardi 2000). The chemical structures required for penetration through the skin are not yet completely understood; yet an approved carrier for skin interaction and transdermal transport is available. The methimazole used in this study was formulated in a lecithin organogel-based vehicle. Lecithin organogels were developed for transdermaltransport of drugs and consist of a ‘spaghetti-like’ network of lecithin micelles, which can host various guest molecules by solubilisation. At this time, the mechanism of transport remains speculative. Lecithin might influence the structure of the skin by disorganising the lipid layers in the stratum corneum (Willimann et al 1992, Luisi et al 1988).

Common side effects in cats on oral methimazole treatment are anorexia, vomiting, and lethargy, as well as unmasking of chronic renal failure, and less frequently to uncommon occurrence of hepatotoxicity, facial excoriations, hematologic changes and rare hypersensitivity reactions as well as development of antinuclear antibodies (Peterson et al 1988). Although not for all of the cats presented here a CBC, chemistry panel, and urine analysis were available for review by the authors and the evaluation for the detection of such adverse effects was not uniform, no adverse effects were seen in this population of patients. This is a promising result because the majority of side effects after oral application develop during the first months of treatment with methimazole (Feldman & Nelson 1996). Metabolism and elimination of methimazole are not well established in the cat. Hepatic metabolism is the major pathway of elimination in humans (Goodman et al 1996, Product informationTapazole®, Eli Lilly, 1998).

Interestingly, two patients in our study (cat 9 and 12) were successfully treated with the transdermal formulation after prolonged periods of vomiting associated with the oral application of methimazole. It remains purely speculative why transdermal delivery did not result in vomiting in these cats. Possibilities might include a bypass of the first pass effect and thus reduction in drug metabolism, slower absorption that might decrease spikes in serum drug concentrations or simply avoidance of contact with the gastrointestinal mucosa.

Due to the necessity of life-long administration of methimazole in hyperthyroid cats, the potential for additional side effects to those described for methimazole in oral formulations is possible. Prolonged dermal application could potentially result in allergic or irritant skin reactions. The study period here might not have been sufficient to identify this likelihood. In addition, personnel applying the drug are potentially exposed to both topical and systemic effects of methimazole and the carrier gel, raising issues of safety. Pet owners should be well informed of appropriate prophylaxis to avoid such contact.

Patient number and treatment periods were limited, rising the likelyhood for overinterpretation of T4 concentrations, which may fluctuate in a range above the coefficient of variation of the assay used (Peterson et al 1987). In addition these results were obtained by retrospective evaluation of medical records from different veterinary hospitals, with loss of follow up information due to owner non-compliance and, in one case, euthanasia on owner request. In addition we do not know whether methimazole gel may have been ingested orally by the cats during grooming. Despite these facts, the results of this study are promising because significant decreases in thyroxine concentrations were noted and progressive concurrent disease leading to euthyroid sick syndrome was unlikely based on clinical and laboratory data. Moreover, clinical improvement was noted in all cases. In two patients (cat 9 and 12), the transdermal route of methimazole application caused no side effects and was successful in controlling disease when side effects had previouslydeveloped with oral treatment.

No adverse effects during transdermal applications over a period of several months were seen in any of the cats of this study. However, the evaluation of side effects of the formulation has limitations, because evaluation of the renal parameters, cardiovascular function, hematologic status, and liver enzyme status were not addressed in a uniform manner. Due to variabilities in their medical workup, the follow-up clinical evaluation is clearly limited and conclusions will need confirmation from further investigations.

The results of this study would support prospective long-term studies in larger populations as well as pharmacokinetic evaluation.