Long-Term Efficacy of Trilostane Administered Twice Daily in Dogs With Pituitary-Dependent Hyperadrenocorticism
Trilostane is considered an efficacious and safe medication for canine pituitary-dependent hyperadrenocorticism (PDH). Its recommended frequency of administration is once daily. In this prospective study, the efficacy, toxicity, and long-term outcome of trilostane administered twice daily per os were evaluated in 44 dogs with PDH. Mean initial dose was 3.1 mg/kg q 12 hours, and mean final dose was 3.2 mg/kg q 12 hours. The final total daily dose was lower than previously reported for once-daily administration. The mean survival time for affected dogs was 930 days.
Introduction
Hyperadrenocorticism is one of the most common endocrine disorders of middle-aged and older dogs. Most dogs (80% to 90%) have pituitary-dependent hyperadrenocorticism (PDH), whereas 10% to 20% have a functional adrenal tumor.1–3 The most commonly used drug for the treatment of PDH is mitotane, which has good efficacy (80%) but also had potential side effects and disadvantages, such as transient hypoadrenocorticism, permanent mineralocorticoid and glucocorticoid deficiency, drug intolerance, and a high frequency of relapses.1,3–5 In the last decade, an active search has been made for alternative treatments to the management of this disease.
Among new alternative treatments, the most promising drug is trilostane, a competitive inhibitor of β-hydroxysteroid dehydrogenase, an enzyme that processes the conversion of pregnenolone to progesterone in the adrenal gland.6 This orally active drug inhibits the synthesis of the end products of the metabolic pathways in which progesterone is involved, including aldosterone and cortisol.6–8 Trilostane has recently been used for the medical treatment of PDH, with a reported efficacy similar to mitotane.3,9–11 Trilostane has also been effective in reducing hypercortisolemia in dogs with functional adrenocortical neoplasia.12,13
In previous studies, medical management of canine PDH with trilostane was attempted with once-daily administration of the drug. A good response and efficacy were obtained in a majority of the cases.9–11,14 However, in dogs for which there is an inadequate duration of the effect, twice-daily dosing has been recommended.9,11,15 Furthermore, a high urinary cortisol/creatinine ratio has been found 24 hours after trilostane administration in dogs with good control of hyperadrenocorticism on a once-daily treatment protocol, suggesting that trilostane does not suppress cortisol concentration throughout the entire day, and some dogs have a period of time when cortisol levels are elevated.11
The aims of this study were to determine the efficacy and toxicity of twice-daily trilostane administration in dogs with PDH and to evaluate its long-term effects.
Materials and Methods
Clinical Cases
Forty-four client-owned dogs were prospectively and sequentially included in the study. Each tentative diagnosis of hyperadrenocorticism was based on history, physical examination findings, and the results of hematological tests, biochemical profiles, and urinalyses. An adrenocorticotropic hormone (ACTH) stimulation test was carried out in each case. Additionally, a low-dose dexamethasone suppression (LDDS) test and/or a urinary cortisol:creatinine ratio (UCCR) combined with an oral high-dose dexamethasone suppression (HDDS) test were performed to confirm the diagnosis. All dogs underwent abdominal ultrasonography for evaluation of the adrenal glands and the presence of concurrent disorders or complications related to hyperadrenocorticism. The distinction between pituitary-dependent hyperadrenocorticism and a functional adrenal tumor was based on the ultrasonographic appearance of the adrenal glands and/or the results of a standard HDDS test. Only dogs with PDH were included in the study.
Diagnostic Tests
A complete blood cell count (CBC), urinalysis, and a biochemical profile including blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), alanine aminotransferase (ALT), glucose, sodium, potassium, and chloride were performed in each dog at the begining of the study. All ACTH stimulation tests were performed by measuring serum cortisol concentrations before and 1 hour after intravenous (IV) injection of 5 μg/kg tetracosactide.a Hyperadrenocorticism was confirmed by the demonstration of an exaggerated cortisol response after ACTH administration (cortisol >19 μg/dL; reference range 6 to 19 μg/dL).
The LDDS test was also used to confirm hyperadrenocorticism and consisted of measuring cortisol levels before and 4 and 8 hours after dexamethasoneb administration (0.01 mg/kg IV). Failure to suppress cortisol concentration adequately 8 hours after dexamethasone (cortisol >1.4 μg/dL; reference range 0.1 to 1.4 μg/dL) was considered compatible with hyperadrenocorticism. Dogs with cortisol suppression (<1.4 μg/dL or <50% of basal cortisol concentration) at 4 hours and those with high cortisols (>1.4 μg/dL or >50% of basal cortisol concentration) at 8 hours were considered to have PDH.
A UCCR combined with an oral HDDS test consisted of first determining the UCCR in two consecutive morning urine samples. The presence of an elevated UCCR (>60 × 10−6; reference range 10 to 60 × 10−6) in the samples was considered consistent with hyperadrenocorticism. After collection of the second urine sample, animals received three doses of dexamethasone (0.1 mg/kg per os [PO]) at 8-hour intervals, and a third morning urine sample was collected to determine another UCCR. The UCCR of the third urine sample was used to assess adrenal suppression. A final UCCR <50% of the basal UCCR was considered consistent with PDH.
The IV HDDS test consisted of measuring serum cortisols before and 8 hours after dexamethasone (0.1 mg/kg IV). The suppression of serum cortisol at 8 hours to <50% of the basal concentration was considered consistent with PDH. Additionally, ultrasonographic evaluation of the adrenal glands was used to differentiate PDH from adrenal neoplasia. Mild bilateral enlargement of the adrenal glands was considered indicative of PDH.
All cortisol concentrations were determined using an Automated Chemiluminiscence System,c validated for use in the dog.
Treatment and Follow-Up Protocol
The initial dose of trilostane for dogs weighing <5 kg was 15 mg PO q 12 hours. Dogs weighing 5 to 20 kg were given 30 mg PO q 12 hours; dogs weighing 20 to 40 kg received 60 mg PO in the morning and 30 mg PO in the evening; and dogs weighing >40 kg received 60 mg PO q 12 hours.
Dogs were reevaluated at 7 days and at 1, 3, and 6 months after initiation of treatment and every 6 months thereafter or as clinically indicated. Dogs that died before 6 months of treatment were also included in the study. During recheck visits, owners were questioned about their dog’s general well-being, changes in clinical signs, and any potential side effects. A physical examination, CBC, biochemical profile, and an ACTH stimulation test were performed at every visit.
At the first reevaluation, the ACTH stimulation test was performed 4 to 6 hours after the administration of trilostane in order to evaluate the maximum effect of the drug. An improvement of clinical signs (e.g., decreased polyuria, polydipsia, polyphagia) and a post-ACTH cortisol concentration between 1 and 5 μg/dL were considered to be a good response, and the dosage of trilostane was unchanged. If polyuria, polydipsia, and polyphagia persisted and the post-ACTH cortisol concentration was >5 μg/dL, the dosage of trilostane was increased by 25% to 50%. If the dog had weakness, anorexia, vomiting, or diarrhea and a post-ACTH cortisol concentration of <1 μg/dL, trilostane was discontinued for 2 days and the dosage was decreased by 25% to 50%. If the dog continued to show signs of hypoadrenocorticism after the dose reduction, trilostane was stopped for 3 days and an ACTH stimulation test was performed to evaluate the need for a further decrease in the dose versus the need for glucocorticoid and mineralocorticoid supplementation.
At each subsequent examination, the ACTH stimulation test was performed 8 to 12 hours after trilostane administration in order to evaluate the duration of the trilostane effect on cortisol reserves. The trilostane dosage was adjusted based on clinical signs and post-ACTH cortisol concentrations. When dogs had polydipsia, polyuria, polyphagia, and an elevated post-ACTH cortisol (>9 μg/dL), the trilostane dose was increased. When dogs were presented with weakness, anorexia, vomiting, or diarrhea, and low post-ACTH cortisol (<1 μg/dL), the trilostane dose was reduced.9
Statistical Analysis
Descriptive clinical and laboratory data and adrenal function tests were analyzed using a statistical software package.d The outcomes (survival times) for all dogs were analyzed from the initiation of trilostane administration until June 2004. A Kaplan-Meier survival curve was calculated, with censorship of dogs alive at the completion of the study. A P value of <0.05 was considered significant.
Results
Clinical Cases
Forty-four dogs diagnosed with PDH were included in the study between January 2002 and June 2004 at the Clínica Veterinaria Atlántico (Las Palmas de Gran Canaria, Spain) (n=16) and the Veterinary Teaching Hospital of Madrid (Madrid, Spain) (n=28). Ages of the animals ranged from 6 to 14 years, with a mean of 9.9 years. Body weights at the beginning of the study ranged from 4.8 to 49 kg (mean 13.5 kg). There were 30 females (two spayed) and 14 males (one castrated). Represented breeds included the mixed-breed dog (n=12), miniature poodle (n=7), Yorkshire terrier (n=6), boxer (n=4), wirehaired fox terrier (n=3), dachshund (n=3), and one each of Scottish terrier, German shepherd dog, shih tzu, Portuguese water dog, Spaniel Breton, Bedlington terrier, English cocker spaniel, beagle, and miniature schnauzer.
The most common clinical signs initially reported were polyuria (n=41), polydipsia (n=38), polyphagia (n=37), panting (n=29), lethargy (n=29), weakness (n=27), weight gain (n=21), abdominal distension (n=33), dermatological abnormalities (e.g., alopecia, thin skin, hyperpigmentation) (n=26), and liver enlargement (n=26). Concurrent conditions included mammary gland tumors (n=9), mild to moderate congestive heart failure (n=4), chronic allergic skin problems (n=3), cryptorchidism (n=2), renal disease (n=2), gallbladder mucocele (n=2), and diabetes mellitus (n=1).
Diagnostic Tests
Results of the CBCs performed at the beginning of the study showed that the mean ± standard deviation (SD) hematocrit was 49.5±6.3% (range 38% to 65%); the mean leukocyte count was 10.3±3.0 × 103/μL (range 5.4 to 19.5 × 103/μL); and mean platelet count was 462±170 × 103/μL (range 175 to 870 × 103/μL). Results of the serum biochemical panels showed that the mean BUN was 20.9±15.8 mg/dL (range 7.0 to 70.6 mg/dL) and mean creatinine was 0.7±0.3 mg/dL (range 0.3 to 2.4 mg/dL). Mean glucose was 118.5±49.2 mg/dL (range 65.0 to 397.0 mg/dL). Mean total protein was 7.7±0.97 g/dL (range 5.0 to 10.2 g/dL); mean ALP was 1254.5±1313.0 U/L (range 75.0 to 4885.0 U/L); and mean ALT was 145.1±148.8 U/L (range 28.8 to 874.0 U/L). Mean chloride concentration was 112.1±5.2 mEq/L (range 105.0 to 128.0 mEq/L); mean potassium was 4.6±1.4 mEq/L (range 3.6 to 6.0 mEq/L); and mean sodium was 149.4±6.99 (range 139.0 to 171.2 mEq/L). Mean calcium was 9.9±0.7 mg/dL (range 8.8 to 11.0 mg/dL), and mean cholesterol was 379.1±207.3 mg/dL (range 200.0 to 880.0 mg/dL). In 40 dogs, urine specific gravity was <1.030.
At the start of the study, leukocytosis (i.e., total white blood cells >17 × 103/μL) was observed in 10 dogs, and neutrophilia (>12 × 103/μL) was seen in 27 dogs. Six months after trilostane administration, leukocytosis persisted in one dog. Seven dogs had erythrocytosis at the beginning of the study, but this finding was present in only one dog after 6 months of therapy. Before trilostane administration, BUN was elevated (>26 mg/dL) in seven dogs. At 6 months, two of these dogs had died, BUN was unchanged in three dogs, and two additional dogs had developed elevations in BUN. Median values for ALP and ALT were significantly lower than pretreatment values at each reevaluation [Table 1].
Based on initial ACTH stimulation tests, the mean (± SD) basal cortisol concentration before ACTH administration was 7.4±4.7 μg/dL (range 1.2 to 25.5 μg/dL), and the mean post-ACTH cortisol concentration was 36.3±14.9 μg/dL (range 18.7 to 78.0 μg/dL). The UCCR was evaluated in 16 dogs at the start of the study. The basal UCCR ranged from 64 to 2660 × 10−6, with a mean of 709±770 × 10−6. The UCCR obtained after the oral HDDS test was <50% of the basal UCCR in all 16 dogs. The LDDS test was assessed in nine dogs and was consistent with a diagnosis of hyperadrenocorticism in all nine, with a mean 8-hour cortisol concentration of 7.4±5.6 μg/dL (range 2.9 to 18.0 μg/dL). The HDDS test was performed in nine dogs and indicated PDH in five dogs. In the remaining four dogs, symmetrical and bilateral enlargement of adrenal glands (i.e., thickness of adrenal glands >7 mm) was consistent with PDH.
Treatment Evaluations
The mean (± SD) initial dose of trilostane was 6.2±2.6 mg/kg (range 2.4 to 15.0 mg/kg) divided twice daily. This initial dosage was not changed throughout the course of the study in 10 dogs, was increased in 19 dogs, was reduced in five dogs, and was both increased and reduced in 10 dogs.
At the 1-week reevaluation, polydipsia and polyuria had improved in 38 (86%) dogs. In 14 dogs, polyphagia persisted. Eight dogs with polydipsia/polyuria and/or polyphagia had post-ACTH cortisol concentrations >10 μg/dL, and the dose of trilostane was increased by 25% to 50%. Five dogs had gastrointestinal signs. These signs were mild (i.e., decreased appetite) in three dogs and moderate (i.e., anorexia and vomiting) in two dogs, and the trilostane dose was reduced in all five dogs. The mean (± SD) basal cortisol concentration in the 44 dogs tested was 4.0±3.3 μg/dL (range 0.2 to 12.9 μg/dL), and the mean post-ACTH cortisol concentration was 7.4±6.1 μg/dL (range 0.3 to 23.0 μg/dL). After this first reevaluation, the mean (± SD) dose of trilostane was 6.4±3.2 mg/kg (range 2.4 to 18.7 mg/kg).
At the 1-month evaluation, polydipsia and polyuria had resolved in all dogs. In 10 dogs, polyphagia was still present and the post-ACTH cortisol concentrations were >9 μg/dL, so the dosage of trilostane was increased. In two cases, mild to moderate gastrointestinal signs were present (i.e., reduced appetite, vomiting), and the post-ACTH cortisol concentration was <1.2 μg/dL. In both of these dogs, trilostane was discontinued for 3 days and then restarted at a reduced dosage. The mean (± SD) basal cortisol concentration in the 37 dogs tested was 3.9±2.4 μg/dL (range 0.4 to 9.5 μg/dL), and the mean post-ACTH cortisol concentration was 9.6±5.2 μg/dL (range 0.8 to 22.2 μg/dL). After the 1-month reevaluation, the mean dose of trilostane was 6.7±3.4 mg/kg (range 2.5 to 16.6 mg/kg).
At the 3-month evaluation, three dogs had polydipsia or polyuria, and 10 dogs still had polyphagia. The dose of trilostane was increased in the latter 10 dogs, because they had clinical signs and an elevated post-ACTH cortisol value (>9 μg/dL). One dog had a reduced appetite and a post-ACTH cortisol of 1.8 μg/dL, so the trilostane dose was reduced and the dog responded well. The mean (± SD) basal cortisol concentration in the 36 dogs tested was 3.4±1.9 μg/dL (range 0.4 to 9.8 μg/dL), and the mean post-ACTH cortisol concentration was 8.7±4.7 μg/dL (range 1.3 to 18.0 μg/dL). The mean dose of trilostane after this evaluation was 7.5±4.0 mg/kg (range 2.5 to 16.6 mg/kg).
At the 6-month evaluation, many clinical signs such as weakness, panting, lethargy, thin skin, and alopecia had resolved, although slight abdominal distension was evident in some dogs. Three dogs had polydipsia and/or polyuria, while polyphagia persisted in four cases. The dosage of trilostane was increased in five of these seven dogs. Three additional dogs required a reduction in the trilostane dose because of decreased appetite, shivering and weakness, or ataxia and generalized involuntary movements. The dog with ataxia and involuntary movements had severe hyponatremia. In three dogs, serum post-ACTH cortisol values ranged from 0.8 to 2 μg/dL. For the 30 dogs tested at this time, the mean (± SD) basal cortisol concentration was 3.6±1.9 μg/dL (range 0.1 to 8.4 μg/dL), and the mean post-ACTH cortisol concentration was 7.5±5.2 μg/dL (range 0.3 to 20.0 μg/dL). The mean dose of trilostane after the 6-month evaluation was 7.4±4.1 mg/kg (range 2.6 to 18.1 mg/kg).
At the 1-year evaluation, adjustments in dosages were required in five dogs. Three dogs needed an increase, and trilostane was stopped in two dogs because of clinical signs of hypoadrenocorticism and pre- and post-ACTH cortisol values <1 μg/dL. For the 24 dogs tested at this time, the mean (± SD) basal cortisol concentration was 3.2±2.8 μg/dL (range 0.1 to 13.1 μg/dL), and the mean post-ACTH cortisol concentration was 6.2±6.1 μg/dL (range 0.1 to 26.2 μg/dL). The mean dose of trilostane after this evaluation was 8.3±4.2 mg/kg (range 2.1 to 18.1 mg/kg).
At the 1.5-year evaluation, the trilostane dosage was reduced in one dog and increased in one dog based on clinical signs and adrenal function tests results. In two additional dogs, severe clinical signs of hypoadrenocorticism with hyperkalemia and hyponatremia were present after 15 and 18 months of treatment, respectively. Cortisol levels before and after ACTH were <0.5 μg/dL, and trilostane was stopped in these two dogs. The mean (± SD) basal cortisol concentration for the 18 dogs tested was 2.7±2.4 μg/dL (range 0.4 to 10.0 μg/dL), and the mean post-ACTH cortisol concentration was 4.7±4.4 μg/dL (range 0.5 to 18.3 μg/dL). The mean dose of trilostane after this evaluation was 6.9±5.1 mg/kg (range 2.8 to 20.4 mg/kg).
At the 2-year evaluation, the trilostane was stopped in one dog with weakness, anorexia, vomiting, and diarrhea; in all other dogs, the dose of trilostane was not modified. The mean (± SD) basal cortisol concentration in the 11 dogs tested was 2.3±2.6 μg/dL (range 0.2 to 9.2 μg/dL), and the mean post-ACTH cortisol concentration was 4.1±3.8 μg/dL (range 0.5 to 11.2 μg/dL). The mean dose of trilostane after this evaluation was 6.5±5.7 mg/kg (range 2.1 to 20.4 mg/kg).
At a 2.5-year evaluation, trilostane was reduced in two dogs and increased in one dog. Mean basal cortisol in the six dogs tested was 2.5±2.3 μg/dL (range 0.5 to 6.3 μg/dL), and mean post-ACTH cortisol was 5.6±5.8 μg/dL (range 0.5 to 16 μg/dL). The mean dose of trilostane after this examination was 4.9±4.4 mg/kg (range 1.3 to 13.1 mg/kg).
For economical reasons, some dogs were changed to mitotane after 3 months (n=2), 1 year (n=1), 2.5 years (n=1), and 2.75 years (n=1). Results of ACTH stimulation tests performed throughout the study are summarized in Table 2.
Adverse Reactions
Eleven (25%) dogs had one or more episodes of shivering, weakness, reduced appetite, anorexia, vomiting, or diarrhea at different times throughout the study. These dogs all had basal and post-ACTH cortisol values <2 μg/dL. Electrolyte abnormalities (i.e., hyperkalemia and/or hyponatremia) occurred in approximately half of these episodes, and all dogs responded well to the administration of IV fluids and glucocorticoids, including a dog that developed severe hyponatremia after 6 months of trilostane treatment. In five (11% of the total) of these 11 dogs, trilostane treatment was indefinitely discontinued because of prolonged depression of cortisol values after 1 year (n=2), after 1.5 years (n=2), and after 2 years of treatment (n=1). In four of the five dogs, adrenal function recovered sufficiently after several weeks, and they are currently doing well on no therapy. The remaining dog has needed long-term glucocorticoid and mineralocorticoid supplementation.
Outcomes
The minimal follow-up period was 6 months, and the maximal follow-up period was 3.5 years (mean 21 months). Twenty-nine dogs were still alive at the time of writing. Of the 15 dogs that died, eight succumbed from unrelated diseases, including metastatic mammary tumors (n=2), severe hip arthrosis (n=2), renal failure and diabetic ketoacidosis (n=1), gastric neoplasia (n=1), cardiac failure (n=1), and pneumonia (n=1). Two additional dogs died from complications of hyperadrenocorticism, biliary peritonitis from a gallbladder mucocele, and growth of a pituitary macroadenoma. In four cases, the cause of death was unknown. One dog was lost for follow-up after 1 month of treatment. The mean survival time for the 43 dogs followed was 930 days (mean ± SD was 31±2 months; 95% confidence interval was 26 to 36 months) [see Figure].
Discussion
Hyperadrenocorticism is one of the most common endocrine disorders of older dogs. In the last decade, several studies have focused on the search for alternative treatments to the classical drug, mitotane. So far the most effective alternative is trilostane, which has fewer adverse effects compared with mitotane.9–11 In prior published clinical studies that evaluated trilostane in dogs with hyperadrenocorticism, the drug was administered once daily.9–11 The duration of trilostane’s effect depends on several factors, such as drug absorption and rate of metabolism.16,17 It has been reported that some dogs need q 12-hour dosing to control the disease.11 When trilostane is administered once daily, the basal cortisol concentration is reduced for only a few hours, but the post-ACTH cortisol concentration is reduced for up to 20 hours.18 It appears that administration of trilostane once daily to dogs with hyperadrenocorticism suppresses cortisol for approximately 20 hours and may lead to elevated cortisol levels during the hours just before administration of the next dose. The clinical study reported here evaluated the efficacy, toxicity, and long-term effects of trilostane administered twice daily in dogs with PDH.
The initial dose (6.2 mg/kg per day) used in the current study was similar to that used by others when trilostane has been administered once daily.9–11 In follow-up evaluations, the dose of trilostane was adjusted in most of the dogs. Overall, the dose was increased in 43% of the dogs, both increased and decreased in 23%, and decreased in 11%. A similar need for dosage adjustments has also been described in dogs receiving once-daily trilostane and in humans taking the drug.9,11,17
The mean dosage needed to achieve good control of PDH remained <10 mg/kg per day throughout the study (7.5 mg/kg per day at 6 months; 8.3 mg/kg per day at 1 year; and 6.5 mg/kg per day at 2 years). The mean final daily dose in the present study was lower than the dose administered in previous studies (i.e., 11.4 and 19 mg/kg).9,11 This difference may be related to the study design (i.e., twice-daily administration with 8- to 12-hour post-pill testing), which was aimed at controlling clinical signs and maintaining cortisol concentrations at physiological levels throughout the day. The goal of treatment in studies using once-daily administration is to achieve a subnormal cortisol response to ACTH during peak trilostane activity (i.e., 4 to 6 hours post-pill). Despite using lower daily doses, trilostane administered twice daily was very effective in controlling the signs of hyperadrenocorticism.
In the current study, larger dogs (>25 kg) needed a smaller dose per kg to control clinical signs when compared to smaller dogs. This difference has also been found in other studies and may be explained by differences in metabolic rates.11 It is interesting to note that Yorkshire terriers needed higher doses of trilostane (mean dose of 13.4 mg/kg) than other breeds to control their clinical signs. Among the six dogs of this breed, five required an increase in the initial dose, and the final dosage that provided good control of the disease was higher than the mean dosage for the whole study.
The efficacy of trilostane in the management of PDH in this study was similar to that described in other reports evaluating trilostane and/or mitotane.1,4,9–11 Trilostane has greater efficacy than other drugs used to treat PDH, such as L-deprenyl (25%) and ketoconazole (25% to 70%).1,19 After 1 week of treatment, polydipsia, polyuria, and polyphagia improved in 82% of the dogs in the current study, and these dogs had post-ACTH cortisol values performed 4 to 6 hours post-pill.
At the later evaluations done during the study, ACTH stimulation tests were performed 8 to 12 hours after trilostane administration. Post-ACTH cortisol concentrations can be expected to vary with the interval between dosing and testing.20 When an ACTH stimulation test is performed >6 hours post-pill in dogs receiving trilostane once daily, cortisol concentrations of 1.0 to 9.0 μg/dL have been recommended as indicators of good control.9 Most dogs with cortisol concentrations in the low end of this range do well, because the cortisol suppression lasts only a few hours and cortisol concentration slowly increases before the next trilostane dose is administered. In the present study, however, some dogs with post-ACTH cortisol concentrations between 1.0 and 2.0 μg/dL had signs of hypoadrenocorticism, perhaps because twice-daily trilostane administration does not allow cortisol concentrations to rise as much before the next administration. Based on the results of this study, when testing dogs on twice-daily trilostane (8 to 12 hours post-pill), a post-ACTH cortisol concentration between 2.0 and 10.0 μg/dL correlated well with good clinical control of the disease. The cortisol values of this range are slightly higher than previously recommended ranges when trilostane was administered once daily.9–11 This range is also considerably higher than the recommended range (1 to 4 μg/dL) in dogs receiving mitotane for hyperadrenocorticism, in which only partial adrenal necrosis is desirable.4 Dogs on mitotane treatment can be symptomatic with post-ACTH cortisol concentrations between 5 and 10 μg/dL; however, dogs receiving twice-daily trilostane treatment are usually well controlled at this range.
Adverse effects experienced by the dogs of this study were similar to those described previously.9–11 Approximately 25% of the treated dogs had at least one episode of hypoadrenocorticism. Some dogs showed clinical signs with borderline low cortisol concentrations, while others remained asymptomatic with low to undetectable cortisol levels. Because of this individual variation, it is advisable to perform examinations every 3 to 6 months in dogs receiving trilostane, even when the dog is clinically normal.
Prolonged suppression of cortisol levels has been reported from trilostane in several studies.9,11,21 In the study reported here, trilostane treatment was permanently discontinued in 11% of dogs (n=5), although only 2% of the dogs needed long-term glucocorticoid and mineralocorticoid supplementation. One case report described adrenal cortical necrosis with reactive inflammation and fibrosis in a dog receiving trilostane for hyperadrenocorticism, but histological evaluation of adrenal glands was not performed in the present study.22 According to the current study, as well as a previous paper, prolonged hypoadrenocorticism is more likely to occur in dogs that have been receiving trilostane for >1 year.11
The mean survival time achieved with trilostane administered twice daily (930 days) was higher than that reported with once-daily administration (540 days) and that obtained with mitotane (803 days).4,9 Ideally, survival time should be calculated after all individuals have died; but in the current study, many dogs (66%) were still alive at the time of writing.
Based on the results of this study, twice-daily trilostane administration was an effective and safe alternative to mitotane and trilostane administered once daily. The basal and post-ACTH cortisol concentrations observed in dogs with well-controlled disease were slightly higher than those published previously. Despite twice-daily administration being less convenient for the owner, it was beneficial for several reasons. The dosages that were needed to achieve good control of the disease were lower than those needed when the drug was administered once daily, and the more physiological cortisol concentrations achieved throughout the day may be an advantage, especially during stressful situations.
Conclusion
Twice-daily trilostane administration to 44 dogs with PDH was safe and effective. A major advantage compared with once-daily administration was the lower dosage needed to control the disease. Further studies are warranted to better understand the effects of trilostane on the adrenal gland and its long-term efficacy and safety in dogs with hyperadrenocorticism.
Synacthène; Novartis Pharma Schweiz AG, Bern, Switzerland
Caliercortin; Calier Laboratories, Barcelona, Spain
ACS: 180; Chiron Diagnostics, Walpole, MA 02032
SPSS 12.0; SPSS, Inc., Chicago, IL 60606
Acknowledgment
The authors thank Dr. Pedro Cuesta for his statistical analysis support.
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420269
Kaplan-Meier survival curve for 44 dogs with pituitary-dependent hyperadrenocorticism treated with trilostane twice daily. Dogs alive (n=29) and lost to follow-up (n=1) were censored.
Contributor Notes
