Naturally occurring hyperadrenocorticism (NOH) is a well-recognized endocrine disorder in dogs. Approximately 85% of dogs with NOH have a pituitary tumor that secretes excessive amounts of ACTH autonomously. This autonomous ACTH secretion results in secondary adrenocortical hyperplasia and chronic excesses in cortisol secretion, called pituitary-dependent hyperadrenocorticism (PDH). Trilostane is a 4α, 5-epoxysteroid competitive inhibitor of the 3ß-hydroxysteroid dehydrogenase-isomerase enzyme system. After oral administration, trilostane inhibits metabolic pathways involving progesterone, blocking the synthesis of end products including cortisol and aldosterone. Trilostane is commonly used for the treatment of PDH in dogs.[3-10] The oral trilostane dosage recommended by the manufacturer for treatment of PDH in dogs is approximately 3–6 mg/kg (1.36–2.73 mg/lb) given once daily.1 In dogs with an inadequate duration of effect, 2 or 3 times daily dosing regimens have been recommended.[3, 4, 8-10] A large majority of dogs treated with trilostane improve.[3-10] Worrisome adverse effects, typically caused by hypocortisolism, although mineralocorticoid deficiencies also have been documented, have been reported in a minority of dogs treated with trilostane.[3-9],2 Usually, adverse effects include anorexia, vomiting, diarrhea, or weakness, but several dogs have died from the effects of trilostane.[3-9],1,2
After demonstrating a rapid but transient response (<12 hours) to trilostane in dogs and also considering the incidence of serious adverse effects caused by trilostane, as reported by several authors and the company distributing trilostane,[3-9],1,2 investigations of the efficacy of lower doses were undertaken.[9, 10] The recent report on effectiveness of lower dose trilostane treatment, given 2 or 3 times daily, for NOH prompted questions regarding dose relative to body weight.3 Specifically, it was suggested that smaller dogs (<15 kg) might require larger doses of trilostane/kg of body weight and are relatively resistant to trilostane as compared with larger dogs (>15 kg), who might require smaller doses/kg and are relatively sensitive to the drug.
To evaluate the proposition that body weight might be associated with trilostane sensitivity and therefore dosage, dogs with PDH previously treated and reported were studied.[9, 10] For inclusion, the diagnosis of NOH in each dog must have been suspected from review of historical data and physical examination results. Each dog must have had polyuria as an owner concern, and each dog must have had at least 4 of 6 clinicopathologic findings: serum activity of alkaline phosphatase above the reference range, serum activity of alanine aminotransferase above the reference range, serum cholesterol concentration above the reference range, serum urea nitrogen (SUN) concentration below or in the lower half of the reference range, urine specific gravity <1.020, and microbial growth on culture of urine. No dog had a SUN concentration >25 mg/dL and none had received prior treatment for NOH. Before initiation of trilostane administration, each dog must have had an abdominal ultrasonographic examination.4 For each dog, results of at least 2 of 3 screening tests (ie, ACTH stimulation test, low-dose dexamethasone suppression test [LDDST], or urine cortisol: creatinine ratio [UCCR]) must have been consistent with NOH. Not all dogs underwent all 3 screening tests. The diagnosis of PDH was made if a dog had at least 2 of the following 3 diagnostic test results: a LDDST result indicative of PDH, ultrasonographic evidence of 2 relatively equal-sized adrenal glands with no evidence of an adrenal gland tumor, or plasma concentration of endogenous ACTH >45 pg/mL.[9, 10] Each dog included must have been treated with trilostane for at least 6 months. Each must have had a “good response” based on owner observations and a serum cortisol concentration ≥1 μg/dL after ACTH stimulation ( to minimize risk of over dose). Good response was defined as resolution of or marked improvement in clinical signs related to PDH (ie, reduction in or absence of polydipsia, polyuria, polyphagia, panting, and an increase in muscle strength and activity). Seventy dogs met the inclusion criteria. Each dog's trilostane dose and frequency of administration were that recorded after at least 6 months of treatment with a good response in resolving the clinical signs of PDH without causing negative adverse effects. The range [and median] of serum cortisol concentrations before and after ACTH stimulation, from all 70 dogs at the time that clinical signs were well controlled, were 0.6–6.8 μg/dL [1.6] and 1.0–9.4 μg/dL [2.3], respectively.
Trilostane dose (mg/kg/dose) and dosage (mg/kg/day) were evaluated using an exact Jonckheere-Terpstra test for evidence of a trend across ordered weight categories (dose-response). Pairwise comparisons between weight categories were performed using an exact Wilcoxon-Mann-Whitney test. The functional relationship between the amount of trilostane administered each day and weight (kg) was evaluated using fractional polynomial regression. The hypothesis that larger dogs might require lower doses per kg of body weight than smaller dogs implies that metabolic body weight or body surface area (BSA) be considered when determining trilostane dose. Therefore, in addition to the analyses described, all were repeated using BSA. StatXact-8 and Stata/IC 10.1 were used for statistical analyses.56 P-values <.05 were considered statistically significant.
In the initial assessment, the 70 dogs with PDH were divided by weight into 2 groups: dogs weighing ≤15 kg of body weight (30 dogs; median body weight: 10.0 kg) and dogs weighing >15 kg (40 dogs; median body weight: 29.9 kg). There was no significant difference (P = .29) in the dose required to control PDH in the 2 groups, with the mean (median, ± SD) dose for the smaller dogs being 1.73 mg/kg (1.4, ± 1.0) and that for the larger dogs being 1.61 mg/kg (1.1, ± 1.1; P = .29; BSA: P = .069 for individual doses). In the group of 30 dogs weighing ≤15 kg, 3 were given trilostane once daily, 24 were given the drug twice daily, and 3 were given the drug 3 times daily. In the larger dogs, 2 were given the drug once daily, 32 were given the drug twice daily, and 6 were given the drug 3 times daily. Therefore, total daily amount of trilostane being administered was evaluated with no significant difference in the total daily dosage required to control the clinical signs of PDH in the 2 groups (P = .57; BSA: P = .25 for total doses). The smaller dogs were given 3.28 mg/kg/day (2.8, ± 1.6) daily and the larger dogs required 3.31 mg/kg/day (2.7, ± 2.2) daily.
The 70 dogs with PDH were then divided into groups consisting of those weighing ≤10 kg of body weight (16 dogs, Group 1; median body weight: 6.4 kg), those weighing 10.1–20 kg (19 dogs, Group 2; median body weight: 14.2 kg), those weighing 20.1–30 kg (16 dogs, Group 3; median body weight: 26.1 kg), and those weighing >30 kg (19 dogs, Group 4; median body weight: 39.2 kg). The mean dose in the Group 1 dogs was 1.81 mg/kg (1.3, ± 1.2), in the Group 2 dogs it was 1.80 mg/kg (1.4, ± 0.81), in the Group 3 dogs it was 1.89 mg/kg (1.2, ± 1.4), and in the Group 4 dogs it was 1.19 mg/kg (0.95, ± 0.68). Although there was a close-to-significant difference in trilostane dose requirement (mg/kg) for dogs across the 4 ordered Groups (P = .066; BSA: P = .063), the P value was significant only in comparing the data from the Group 4 dogs with each of the 3 other groups (P = .020; BSA: P = .017), suggesting that dogs weighing >30 kg tend to be more sensitive to trilostane and require less trilostane to control the clinical signs of PDH than dogs weighing <30 kg.
In the Group 1 dogs, 1 was given trilostane once daily and 15 were given the drug twice daily. In the Group 2 dogs, 1 was given trilostane once daily, 15 were given the drug twice daily, and 3 were given the drug 3 times daily. In the Group 3 dogs, 1 was given the drug once daily, 11 were given the drug twice daily, and 4 were given the drug 3 times daily. In the Group 4 dogs, 1 was given the drug once daily, 16 were given the drug twice daily, and 2 were given the drug 3 times daily. The total daily dosage administered to dog Groups 1–4 was 3.2 mg/kg/day (2.4, ± 2.0), 3.7 mg/kg/day (3.9, ± 1.7), 4.0 mg/kg/day (2.0, ± 2.7), and 2.4 mg/kg/day (2.0, ± 1.2), respectively. Although there was no significant difference in the total daily dosage requirement comparing the dogs across ordered groups (P = .21; BSA: P = .21 for total dosage), the P value again was significant in comparing the data from dogs in Group 4 with that of the 3 other groups (P = .025; BSA: P = .023 for total dosage). However, included in each of these 4 groups were individual dogs requiring <1.5 mg/kg/day and each group includes dogs whose total daily dosage requirement was >4.0 mg/kg/day. Regardless, from these data, there is again evidence suggesting that the daily amount of trilostane required for dogs that weigh >30 kg tends to be less than that required for dogs who weigh <30 kg.
Individual sensitivity to trilostane, regardless of body weight, likely contributes to determining the amount of trilostane necessary to resolve clinical signs. However, additional support for the hypothesis that total trilostane daily dosage required to ameliorate the clinical signs of PDH in a dog may be a function of weight can be seen in Figure 1. This regression analysis suggests that total daily dosage is predicted to decline at weights approximately greater than 15 kg. Confidence intervals for both regression coefficients excluded 0: ie, both regression coefficients were significantly different from zero.
Figure 1. Fractional polynomial regression showing the predicted relationship between effective total dosage (mg) and weight (kg). Shaded area represents 95% confidence interval of the line.
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Although the purpose of this follow-up study was to evaluate trilostane dose and dosage versus body weight, it is appropriate to refer back to the manufacturer's initial dosage recommendation of 3–6 mg/kg, once daily. In reviewing the trilostane requirements of the 70 dogs in this study, only 8 of the dogs (11%) required as much as 3 mg/kg/dose: 2 of 16 dogs in the ≤10 kg body weight group; 2 of 19 dogs in the 10.1–20 kg body weight group; 4 of 16 dogs in the 20.1–30 kg body weight group; and 0 of the 19 dogs in the >30 kg body weight group. These data suggest that the 3–6 mg/kg initial trilostane dosage recommendation be reconsidered.