Methimazole (Tapazole) a is an antithyroid drug commonly

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1 J Vet Intern Med 2004;18: Efficacy and Safety of Transdermal Methimazole in the Treatment of Cats with Hyperthyroidism Laura Lee Sartor, Lauren A. Trepanier, Mandy M. Kroll, Ilona Rodan, and Laura Challoner The objective of this study was to determine whether transdermal methimazole was as safe and effective as oral methimazole for the control of hyperthyroidism in cats. Forty-seven cats with newly diagnosed hyperthyroidism were randomized to receive either transdermal methimazole in pluronic lecithin organogel (PLO; applied to the inner pinna), or oral methimazole (2.5 mg q12h for either route). Cats were evaluated at weeks 0, 2, and 4 with a physical exam, body weight determination, CBC, biochemical panel, urinalysis, measurement of total levothyroxine (T 4 ) concentration, indirect Doppler blood pressure determinaiton, and completion of an owner questionnaire. Data between the 2 groups and over time were compared by nonparametric methods. Forty-four cats followed the protocol (17 oral and 27 transdermal). Significantly more cats treated with oral methimazole had serum T 4 concentrations within the reference range after 2 weeks (14 of 16 cats) compared to those treated by the transdermal route (14 of 25; P.027). This difference was no longer significant by 4 weeks of treatment (9 of 11 for oral versus 14 of 21 for transdermal), possibly because of inadequate numbers evaluated by 4 weeks. Cats treated with oral methimazole had a higher incidence of gastrointestinal (GI) adverse effects (4 of 17 cats) compared to the cats treated with transdermal methimazole (1 of 27; P.04), but no differences were found between groups in the incidence of neutropenia, hepatotoxicity, or facial excoriations. Although the overall efficacy of transdermal methimazole is not as high as that of oral methimazole at 2 weeks of treatment, it is associated with fewer GI adverse effects compared to the oral route. Key words: Custom compounding; Feline; PLO; Pluronic lecithin organogel; Thyrotoxicosis. Methimazole (Tapazole) a is an antithyroid drug commonly used in the management of hyperthyroidism in cats. Methimazole inhibits several steps in thyroid hormone synthesis, and is very effective in restoring euthyroidism in most cats. However, 10 20% of cats experience gastrointestinal (GI) upset during methimazole treatment, with hepatotoxicity, neutropenia, thrombocyopenia, or facial pruritus seen less commonly. 1 As with other oral medications, compliance can be a problem in fractious or inappetant cats, and in cats owned by elderly or physically impaired clients. In addition, drug absorption after oral administration may be poor in cats with severe intestinal malabsorption (eg, severe inflammatory bowel disease or lymphoma). Recently, custom veterinary pharmacies have offered methimazole in a pluronic lecithin organogel (PLO) formulation containing lecithin, isopropyl palmitate, and pluronic acid for transdermal administration in cats. We recently reported poor bioavailability of methimazole in PLO administered by the transdermal route in healthy cats after a single dose. 2 However, we and others 3 have observed apparent clinical responses in hyperthyroid cats treated with transdermal methimazole. We hypothesized that the efficacy of transdermal methimazole with chronic dosing would be greater than that predicted by single dose pharmacokinetics. Therefore, the objective of this study was to determine, From the University of Wisconsin Madison School of Veterinary Medicine, Madison, WI (Sartor, Trepanier); and The CatCare Clinic, Madison, WI (Kroll, Rodan, Challoner). Previously presented in abstract form at the 21th Annual American College of Veterinary Internal Medicine Forum, June 4 8, 2003, Charlotte, NC. Reprint requests: Lauren A. Trepanier, DVM, PhD, Dip ACVIM, Dip ACVCP, Department of Medical Sciences, University of Wisconsin Madison, School of Veterinary Medicine, 2015 Linden Drive, Madison, WI ; latrepanier@svm.vetmed.wisc.edu. Submitted February 9, 2004; Revised May 3, 2004; Accepted May 27, Copyright 2004 by the American College of Veterinary Internal Medicine /04/ /$3.00/0 in a controlled prospective clinical trial, the relative safety and efficacy of methimazole in PLO administered by the transdermal route compared to tablets administered by the oral route in the treatment of cats with naturally occurring hyperthyroidism. Materials and Methods Client-owned cats with newly diagnosed, naturally occurring hyperthyroidism were eligible for the study. The study design was approved by the Institutional Animal Care and Use Committee and all clients gave informed consent. The diagnosis of hyperthyroidism was made on the basis of a high serum total levothyroxine (T 4 ) concentration by radioimmunoassay (reference range for our laboratory, g/dl), along with clinical signs of goiter, weight loss, tachycardia, polyuria, polydipsia, polyphagia, or hyperactivity. No cats were treated with methimazole before the start of the study. Forty-seven cats with newly diagnosed hyperthyroidism were enrolled in the study from October 2001 through September Cats were randomized to receive either transdermal methimazole in PLO (applied to the inner pinna) or oral methimazole in tablet form a (2.5 mg q12h for either route). Randomization was based on the date of 1st diagnosis of hyperthyroidism. Cats 1st seen on an odd day of the week (eg, January 3) were assigned to the transdermal group and cats 1st seen on an even day of the week (eg, January 14) were assigned to the oral group. Methimazole for topical administration was formulated in a transdermal PLO according to guidelines of the Professional Compounding Centers of America (PCCA, personal communication). A lecithin isopropyl palmitate solution was prepared with 100 g of lecithin soya granular b, 100 g of isopropyl palmitate c, and 0.66 g of sorbic acid NF-FCC powder d. Pluronic gel 20% was prepared with 20 g of pluronic F127 NF e, 0.3 g of potassium sorbate NF f, and sufficient purified water to make 100 ml. Transdermal methimazole gel was formulated with 0.15 g of methimazole USP, 0.66 ml of lecithin isopropyl palmitate solution and sufficient pluronic F127 gel 20% to make 3.0 ml. The resulting gel contained methimazole at 5 mg/0.1 ml and was dispensed in 1-mL tuberculin syringes without needles. Methimazole in PLO (0.05 ml) was applied as a thin layer to the nonhaired portion of the inner pinnae, using alternate ears with each dose. Owners wore finger cots or examination gloves during gel application. Cats were evaluated at week 0 with a physical exam, body weight determination, CBC, biochemical panel, urinalysis (UA), measurement

2 652 Sartor et al of total T 4 concentration, and indirect Doppler blood pressure determination. In addition, owners completed a questionnaire to assess each cat for polyuria, polydipsia, activity level, appetite, and evidence of vomiting, diarrhea, or facial pruritus. Cats were reevaluated after 2 weeks and 4 weeks of methimazole treatment, to include repeat physical examination; CBC; biochemical profile; UA; measurement of body weight, blood pressure, and total serum T 4 concentration; and owner questionnaire. Laboratory testing for all cats was performed at a central referral laboratory. Criteria for removal of cats from the study included development of significant anemia (hematocrit less than 25%), thrombocytopenia (platelets fewer than 80,000/ L), or neutropenia (neutrophils fewer than 1,500/ L); abnormal activities of serum alanine aminotransferase (ALT) or alkaline phosphatase (SAP), with at least a 2-fold increase compared to week 0; development of hyperbilirubinemia; an increase in serum creatinine concentration to 3.0 mg/dl with clinical signs of illness; persistent vomiting or anorexia; or the development of facial excoriation. The antihypertensive agent amlodipine (0.625 mg per cat once daily) 4 was prescribed, according to clinician discretion, for cats with systolic blood pressure measurements greater than mm Hg. g,5 Cats treated with amlodipine were not included in comparisons of blood pressure responses between groups. Data between the 2 groups were compared by Mann-Whitney-Wilcoxon rank sum (numerical data) or chi-square (categorical data) tests by using a commercial software program. h Changes in clinical variables over time were compared by a Friedman 2-way analysis of variance by ranks, followed by pair-wise comparisons by using the Wilcoxon signed-ranks test. 6 Significance was set at P.05. All data are reported as median values with observed ranges given in parentheses. Results Forty-seven cats were enrolled in the study, including 23 from the University of Wisconsin Madison Veterinary Medical Teaching Hospital and 24 from the CatCare Clinic in Madison, WI. Of 47 cats enrolled in the study, 44 cats followed the protocol (17 in the oral group and 27 in the transdermal group). Of the 3 cats that were removed from the study by their owners (all before the week 2 recheck), 1 owner decided to pursue radioiodine therapy (transdermal group), 1 cat was diagnosed with lymphoma (transdermal group), and 1 owner requested euthanasia without further diagnostic follow-up (oral group). No significant differences were found between groups at enrollment regarding initial serum T 4 concentration, body weight, methimazole dosage (mg/kg), heart rate, or indirect systolic blood pressure (Table 1). Serum ALT activity was slightly higher before treatment in the transdermal group compared to the oral group (122 U/L versus 77 U/L, respectively; P.04), but no other biochemical or hematologic differences were found between the groups at baseline. Response over Time A significant decrease in serum T 4 concentration occurred in both groups over the 4 weeks of the study (P.001; Fig 1), with a concomitant decrease in SAP (both groups; P.001) and ALT (transdermal group; P.002) activities. Median body weight and median heart rate did not decrease significantly over time in either group. Excluding 3 cats treated with amlodipine, systolic blood pressure decreased, but not significantly, over the course of the study. Most cats (31 [78%] of 40 for which accurate baseline measurements could be obtained) had systolic blood pressure measurements of 180 mm Hg at the time of diagnosis. Serum creatinine concentrations increased slightly but significantly in both groups over time for those cats that were treated for the entire 4 weeks (a median increase of 0.4 mg/dl for the oral group and 0.2 mg/dl for the transdermal group; each P.04 compared to baseline), but no significant difference was found between groups in this change (P.29). Urine specific gravity did not change significantly over time, and no cat developed clinically significant renal decompensation during treatment. However, blood urea nitrogen did increase significantly in the oral group only (24 mg/dl at baseline to 32 mg/dl at 4 weeks; P.002), a difference that was not seen in the transdermal group. Efficacy between Dosing Regimens Serum T 4 concentration was significantly lower at week 2 in cats treated with oral methimazole compared to those receiving methimazole by the transdermal route (2.4 versus 3.4 g/dl, respectively, P.011; Table 1). In addition, significantly more cats in the oral group had serum T 4 concentrations within the reference range (T g/dl) after 2 weeks (14 [88%] of 16) compared to the transdermal group (14 [56%] of 25; P.035; Fig 1; note that 3 cats with adverse effects by week 2 did not have serum T 4 concentrations measured). By week 4, in a smaller sample size, this difference in serum T 4 concentration between oral and transdermal groups (2.3 versus 3.6 g/dl, respectively) was no longer significant (P.11; Table 1). In addition, by week 4 the difference between groups in the percentage of cats that had normalized serum T 4 concentrations was no longer significant (9 [82%] of 11 with oral treatment versus 14 [67%] of 21 with transdermal treatment; P.36; Fig 1). Clinical responses of weight gain, decrease in heart rate, or drop in blood pressure over time also were not significantly different between groups. Toxicity between Dosing Regimens Cats treated with oral methimazole had a higher incidence of GI adverse effects (4 of 17) compared to the cats treated with transdermal methimazole (1 of 27; Table 2). One cat that developed vomiting and anorexia on oral methimazole (and was removed from the study) was subsequently treated with the same dosage of methimazole given by the transdermal route, and became euthyroid with no further GI upset (data not shown). No differences were found between groups in the incidence of hepatotoxicity, facial excoriations, or neutropenia (Table 2). Neutrophil counts in affected cats ranged from 100 1,210 cells/ L. Although no cat developed clinically significant anemia, the cats treated with oral methimazole had a slightly lower hematocrit by week 4 (37.0%) compared to cats treated with transdermal methimazole (40.9%; P.04). Discussion The results of this study indicate that methimazole in PLO administered by the transdermal route is effective in

3 Transdermal Methimazole 653 Table 1. Clinical parameters in hyperthyroid cats treated with oral or transdermal methimazole (2.5 mg q 12 h) over a 4-week study period. Data are given as median (range). Variable Oral Transdermal Methimazole dosage (mg/kg/d) 1.13 ( ) 1.10 ( ) Baseline data (week 0) Urine specifc gravity White blood cell count (/ L) After 2 weeks of treatment Urine specific gravity White blood cell count (/ L) After 4 weeks of treatment Urine specific gravity White blod cell count (/ L) ( ) 202 ( ) 161 ( ) 7.9 ( ) 77 (34 278) 61 (20 122) 1.2 ( ) 24 (14 46) ( ) 40.5 ( ) 8,000 (4,500 22,980) ( ) 180 ( ) 153 ( ) 2.4 ( )** 62 (31 145) 37 (19 108)** 1.3 ( ) 30 (22 45) ( ) 39.1 ( ) 6,355 (1,900 18,530) ( ) 188 ( ) 146 ( ) 2.3 ( )** 62 (38 162) 33 (13 61)** 1.5 ( )** 32 (19 50)** ( ) 37.0 ( ) 6,490 (4,700 44,210) ( ) 200 ( ) 160 ( ) 7.0 ( ) 122 (45 833)* 62 (33 163) 1.3 ( ) 28 (15 49) ( ) 41.7 ( ) 6,600 (4,000 18,530) ( ) 198 ( ) 155 ( ) 3.4 ( )*, ** 85 ( ) 53 (22 178) 1.2 ( ) 27 (17 56) ( ) 41.3 ( ) 5,980 (3,800 16,500) ( ) 180 ( ) 146 ( ) 3.6 ( )** 78 (31 233)** 47 (16 112)** 1.2 ( ) 27 (21 51) ( ) 41.2 ( ) 6,010 (1,900 17,840) SBP, systolic blood pressure; ALT, serum alanine aminotransferase activity; ALP, serum alkaline phosphate activity. * Significantly different (P 0.05) from the oral treatment group at the time point; ** Significantly different (P 0.05) from baseline (week 0) for that treatment group. the treatment of hyperthyroidism in some cats, with fewer GI adverse effects than with oral treatment. However, oral treatment was effective in significantly more cats by 2 weeks of treatment, so that in severely affected cats, the oral route may result in more rapid resolution of the hyperthyroid state. Conversely, although transdermal administration resulted in clinical euthyroidism in most cats by week 4, a lesser effect on serum T 4 concentration occurred compared to oral administration. A follow-up time longer than 4 weeks possibly would have allowed more cats in the transdermal group to achieve serum T 4 concentrations within the reference range. Serum creatinine concentration rose slightly in both groups in this study, but no significant difference was found in the degree of change, and no cat developed renal decompensation during treatment. Serum urea nitrogen concentration increased significantly but modestly in the oral group during treatment, but did not change in the transdermal group, possibly because of less rapid lowering of serum T 4 concentration during the 1st 2 weeks. That fewer cats had serum T 4 concentrations within the reference range by 2 weeks of transdermal treatment is presumably due to decreased and variable bioavailability of methimazole by the transdermal route compared to the oral route. We recently showed poor methimazole absorption after single transdermal dose in healthy cats. 2 We hypothesized that repeated dosing might enhance absorption and lead to clinical response because permeation enhancers

4 654 Sartor et al Table 2. Cumulative adverse events in 44 cats treated with oral or transdermal methimazole for 4 weeks. Number of Cats Affected Adverse Event Simple gastrointestinal Hepatopathy Facial excoriation Neutropenia Oral 4of17 0of17 0of17 2of17 Transermal 1of27* 1of27 2of27 2of27 * Significantly lower incidence than the oral route; P.04. Fig 1. Change in serum levothyroxine (T 4 ) concentration over time in hyperthyroid cats treated with oral methimazole or methimazole in pluronic lecithin organogel applied to the inner pinnae (2.5 mg q12h for either route). For this scatter plot, each point represents a single cat and the central line represents the median. The dotted lines represent the reference range of serum T 4 concentration for our laboratory, g/dl. An asterisk (*) indicates a significantly lower median T 4 concentration compared to that of the transdermal group at week 2. such as lecithin can lead to exfoliation of the stratum corneum 7 and low-grade inflammation. 8 Repeated dosing may lead to a depot of drug in the skin, allowing continuous release into the circulation. We did not attempt to measure peak plasma methimazole concentrations in this study because healthy cats administered methimazole transdermally have plasma concentrations that do not peak at a predictable time after transdermal dosing. 2 However, a comparison of plasma methimazole concentrations between groups would have helped to determine whether the observed differences between groups were attributable to differing bioavailability between formulations. An important finding in this study was the significant reduction in the incidence of GI adverse effects by the transdermal route, suggesting that GI signs are related to direct gastric irritation by methimazole, rather than a central effect mediated by the chemoreceptor trigger zone. The cat that was changed from oral to transdermal methimazole after removal from the study for GI adverse effects suggests that some cats that do not tolerate oral methimazole because of simple GI signs may tolerate the drug by the transdermal route (or, alternatively, by the oral route at a lower dosage). 1 This is in contrast to adverse effects such as high serum liver enzyme activities, blood dyscrasias, or facial excoriation, for which the transdermal route showed no advantage in this study. It is interesting to note that the 1 cat with apparent hepatotoxicity in the study (with an ALT activity of 1,254 U/L at week 2 compared to 220 U/L before methimazole treatment) was in the transdermal group, which suggests that 1st-pass delivery may not be a prerequisite for methimazole hepatotoxicity in cats. The percentage of cats with drug discontinuation because of GI adverse effects during oral dosing in this study was somewhat higher than that reported for methimazole elsewhere. 1 This may be due to the strict criteria for drug discontinuation used in our study, in which vomiting or anorexia required drug discontinuation, without an attempt at decreasing the methimazole dosage. However, it has been reported that a decrease in methimazole dosage can resolve some cases of drug-associated GI adverse effects in hyperthyroid cats. 1 Therefore, it is likely that more cats, particularly those with low-grade GI signs, would have been considered therapeutic successes if individual dose titration had been allowed. The results of this study do not suggest that transdermal methimazole should replace oral methimazole as the treatment of choice for hyperthyroidism in cats. Efficacy at 4 weeks was still not as high with the transdermal route (14 of 21 cats) compared to the oral route (9 of 11 cats), although this was not statistically different in this relatively small population. Given the similar, but significant, differences in serum T 4 concentration seen at 2 weeks with a greater number of cats still enrolled in the study, the difference observed at 4 weeks would likely be significant in a larger number of cats. Our power calculations before the study indicated that 17 cats remaining in each group by week 4 was required to give a 90% chance of finding a difference in serum T 4 concentration of 2.0 g/dl between treatment groups ( 0.05). We did not reach this sample size at week 4 because of a higher than anticipated dropout rate due to adverse effects. As the study was executed, our sample size at week 4 gave only a 74% chance of finding this difference. Custom formulation of methimazole in PLO adds to the cost of treatment, and the formulation that we used for this study was guaranteed to be stable for only 2 weeks according to the PCCA, from which the formulation protocol was obtained. Therefore, owners had to return every 2 weeks for medication refills, which was inconvenient. Although many clients prefer the transdermal route, it can still be difficult to use in some cats that resent having their ears manipulated or the sensation of the gel on their skin. The PLO can crust up between dosings, and in some cats, can cause mild local erythema. Finally, and most importantly, custom veterinary pharmacies use a variety of transdermal vehicles, which may not have same efficacy and safety as the PLO used in this study. This is the 1st controlled study to report the efficacy of a custom-formulated transdermal drug in veterinary patients. Dozens of transdermal formulations are offered by custom veterinary compounding pharmacies, all with essentially no absorption or efficacy data. It is important to note that the results of this study cannot be extrapolated to transdermal formulations of other drugs, because transdermal drug absorption can vary markedly among drugs. How-

5 Transdermal Methimazole 655 ever, the finding that transdermal methimazole is effective in the treatment of hyperthyroidism in many cats is encouraging, and further studies are needed to evaluate the absorption and efficacy of other drugs formulated in PLO. In summary, administration of transdermal methimazole in PLO resulted in serum T 4 concentrations within the reference range in 67% of cats with hyperthyroidism, with fewer GI adverse effects compared to the same dose administered orally. Although transdermal methimazole in PLO does not appear to be as effective overall as oral methimazole, it is a viable therapeutic alternative in the treatment of feline hyperthyroidism. Footnotes a Tapazole, Jones Pharma Inc (now King Pharmaceuticals), Bristol, TN b Lecithin soya grandular, Professional Compounding Centers of America, c Isopropyl palmitate, Professional Compounding Centers of America, d Sorbic acid NF-FCC powder, Professional Compounding Centers of America, e Pluronic F127NF, Professional Compounding Centers of America, f Potassium sorbate NF, Professional Compounding Centers of America, g Hypertension Consensus Panel. Current recommendations for diagnosis and management of hypertension in cats and dogs (report). American College of Veterinary Internal Medicine 20th Annual Forum, Dallas, TX, May 29 June 1, 2002 h Statview, Abacus Concepts Inc, Berkeley, CA. Acknowledgments This study was funded by a grant from the Winn Feline Foundation and with funds from the Companion Animal Fund at the University of Wisconsin Madison. References 1. Peterson ME, Kintzer PP. Methimazole treatment of 262 cats with hyperthyroidism. J Vet Intern Med 1988;2: Hoffman S, Yoder A, Trepanier L. Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats. J Vet Pharmacol Ther 2002;25: Hoffmann G, Marks S, Taboada J, et al. Transdermal methimazole treatment in cats with hyperthyroidism. J Feline Med Surg 2003; 5: Henik R, Snyder P, Volk L. Treatment of systemic hypertension in cats with amlodipine besylate. J Am Anim Hosp Assoc 1997;33: Sparkes A, Caney S, King M, et al. Inter- and intraindividual variation in Doppler ultrasonic indirect blood pressure measurements in healthy cats. J Vet Intern Med 1999;13: Dawson-Saunders B, Trapp R. Basic and Clinical Biostatistics. Norwalk, CT: Appleton & Lange; Ogiso T, Tanino T. Transdermal delivery of drugs and enhancement of percutaneous absorption. Yakugaku Zasshi 2000;120: Dreher F, Walde P, Luisi P, et al. Human skin irritation studies of a lecithin microemulsion gel and of lecithin liposomes. Skin Pharmacol 1996;9: