Trilostane: A Therapeutic Alternative for Canine Cushing’s Disease
Andrea Struble, DVM, MPVM, DACVIM Veterinary Medical Specialists (Campbell)
Trilostane (4-alpha, 5-alpha-epoxy-17-betahydroxy- 3-oxoandrostane-2-alpha-carbonitrile) is a synthetic steroid analogue. It is a competitive inhibitor of 3- beta-hydroxysteroid dehydrogenase, an enzyme that catalyzes several vital steps in the synthesis of cortisol from cholesterol. When therapeutic concentrations of trilostane are present, cortisol synthesis is reduced. Although 3-beta-hydroxysteroid dehydrogenase is also required for the synthesis of aldosterone, production of this mineralocorticoid is generally spared at standard dosages of trilostane. It is believed that the zona glomerulosa (site of aldosterone production) is less sensitive to trilostane.
Trilostane was demonstrated effective in Europe in the late 1990’s and was licensed for use in the UK and Ireland for the treatment of pituitary and adrenal canine Cushing’s disease. More than 85% of dogs have shown both clinical and biochemical improvement after a month of trilostane therapy. Survival times for patients treated with trilostane are reported to be 662- 930 days.
Trilostane is administered orally and appears to be rapidly absorbed. Peak serum concentrations occur 1 1/2 –2 hours after dosing and returns to baseline within 18 hours; inhibition of steroid synthesis is reported to last less than 20 hours. Trilostane undergoes hepatic metabolism and the pharmacokinetics may be altered in patients with hepatic dysfunction. It should not be used in patients with primary hepatic or renal disease and should be used with caution in anemic dogs. Trilostane should not be administered to pregnant or nursing bitches or any animal intended for breeding.
Trilostane is supplied in 10-, 30-, 60- and 120- mg capsules; the initial dosage is based on body weight and is given once a day with food. The dose is then adjusted based on clinical response and ACTH stimulation response tests. Most patients show clinical improvement within seven days with resolution of polyuria/polydipsia and polyphagia. Re-evaluation is recommended within 2 weeks regardless of clinical status. At this time a PE, chemistry panel and ACTH stimulation test is performed. The ACTH stimulation test must be performed within 4-6 hours after administration of trilostane.
Dosage adjustments are based upon patients’ clinical status and post ACTH stimulation cortisol concentrations. Several different ranges have been described, however the general consensus is that a post ACTH stimulation cortisol concentration between 1.5 and 5.5 ug/dl indicates optimal control. The package insert states a range from 1.5 – 9 ug/dl is optimal, however some patients may manifest some clinical signs above 5.5 ug/dl.
If the cortisol concentration is below 0.7, stop the trilostane until signs of Cushing’s recur and monitor for any signs of hypocortisolemia. If the post stimulation cortisol level is 0.7-1.5 ug/dl, stop therapy for 48 hours and then restart at a 50% reduced dosage. Monitoring dogs on trilostane involves repeating the ACTH stimulation and chemistry panel in 2 weeks and then every 3-6 months. A few dogs may continue to demonstrate clinical signs of Cushing’s despite appropriate ACTH stimulation results. If this occurs, the dose should be divided and given twice daily. One recent report indicates that routine twice-daily therapy achieved control of Cushing’s with a lower total daily dose. This twice daily dosing should be attempted if clinical signs are present despite an adequate post ACTH stimulation cortisol result (an indication that the half life in that patient is too short).
Adverse effects have been reported and the most common is a transient hypocortisolemia that manifests as anorexia and lethargy. If this occurs, discontinue trilostane, check a biochemistry and electrolyte panel, and then restart trilostane at a 50% reduction in dosage.
Rarely trilostane has been associated with acute adrenal gland necrosis; the mechanism is not understood. It does not appear to be dose dependent and can occur when therapy is first started or after several months. This complication is permanent and irreversible, and lifelong supplementation of both mineralocorticoids and glucocorticoids will be necessary.
Trilostane has also been used to treat adrenal tumors that are typically resistant to medical therapy. Trilostane has been demonstrated to control the clinical signs of Cushing’s even in dogs with distant metastasis. Trilostane can be given prior to adrenal surgery to potentially decrease surgical morbidity from infection and thromboembolism; it should be discontinued 24 hours prior to surgery.
Currently at VMS, trilostane is the drug of choice for treating dogs with pituitary hyperadrenocorticoism unless there is underlying hepatic or renal disease. Trilostane was recently FDA approved for the use in dogs and is readily available.
Please contact any of the internists at VMS if you have any questions regarding your patients with Cushing’s disease or treating with trilostane.