Trilostane: A therapeutic consideration for canine hyperadrenocorticism - Veterinary Medicine
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Trilostane: A therapeutic consideration for canine hyperadrenocorticism
Choices in medical therapy for dogs with hyperadrenocorticism can be limited. Studies have shown that trilostane provides another option for treating this disease—as well as alopecia X.


VETERINARY MEDICINE


TRILOSTANE


1. The synthesis of steroid hormones. The brown arrows show the site of action of 3-beta-hydroxysteroid dehydrogenase.
Trilostane (4-alpha, 5-alpha-epoxy-17-beta-hydroxy-3-oxoandrostane-2-alpha-carbonitrile) is a synthetic steroid analogue. It is a competitive inhibitor of 3-beta-hydroxysteroid dehydrogenase, an enzyme that catalyses several crucial steps in the synthesis of cortisol from cholesterol (Figure 1).6 When therapeutic concentrations of trilostane are present, cortisol synthesis is dramatically reduced. Although 3-beta-hydroxysteroid dehydrogenase is also required for the synthesis of aldosterone, production of this mineralocorticoid is generally spared at standard therapeutic doses.7 It is thought that the zona glomerulosa (the site of aldosterone production) may be less sensitive to trilostane or that cellular uptake by this region of the adrenal cortex is different.

Trilostane was previously licensed for use in the United States for people with adrenal disorders but was voluntarily removed from the market in 1994. Work done in the late 1990s in Europe demonstrated trilostane's efficacy in managing canine adrenal disease, and it is presently an approved therapy for dogs with adrenal-and pituitary-dependent hyperadrenocorticism in the United Kingdom and Ireland.

Trilostane is administered orally and appears to be rapidly absorbed. Peak serum concentrations occur one-and-a-half to two hours after dosing and return to baseline within 18 hours; inhibition of steroid synthesis is reported to last less than 20 hours.8 Trilostane undergoes hepatic metabolism, and the pharmacokinetics may be altered in patients with liver dysfunction.

The manufacturers state that trilostane should not be used in patients with primary hepatic disease or renal insufficiency.9 It should be used with caution in anemic patients and avoided in pregnant or nursing bitches or any animal intended for breeding.

Starting therapy


Table 6 Dosage Recommendations for Starting Trilostane Therapy
Trilostane is supplied in 10-, 30-, 60-, and 120-mg capsules. The initial dosage is based on body weight (Table 6) and is given once a day with food.9 The dose is then adjusted based on clinical response and ACTH stimulation test results. Most patients show clinical improvement within seven days, with resolution of polydipsia and polyphagia. Re-evaluate all patients, irrespective of clinical status, within the first two weeks. At this time, perform a physical examination, serum chemistry profile including electrolytes, and an ACTH stimulation test. The timing of the ACTH stimulation test is crucial; for the results to be meaningful, it must be started four to six hours after trilostane administration.10

Monitoring

Dose adjustments are based on the patient's clinical status and post-ACTH stimulation cortisol concentrations. Several different target ranges have been described, but the general consensus suggests that a post-ACTH stimulation cortisol concentration between 1.5 and 5.5 μg/dl indicates optimal control.10-12 According to the U.K. package insert, the acceptable post-ACTH stimulation cortisol concentration range is 1.5 to 9 μg/dl,9 but clinical experience indicates that patients may manifest some signs of hyperadrenocorticism at cortisol concentrations above 5.5 μg/dl.


Table 7 Monitoring and Dose Adjustment for Dogs Receiving Trilostane
If the cortisol concentration is below 0.7 μg/dl, withhold trilostane until signs of hyperadrenocorticism recur, and closely monitor the patient for signs of hypocortisolemia.11,13 If the post-ACTH stimulation cortisol concentration is 0.7 to 1.5 μg/dl, suspend therapy for 48 hours, and then restart it with a 50% dose reduction.11,13 If the patient is inadequately controlled, dose increases of 50% to 100% are generally appropriate.11,13 Repeat the clinical evaluation and ACTH stimulation test two weeks after dose adjustment and then every three to six months (Table 7).

A small number of dogs may have a post-ACTH stimulation cortisol concentration within the optimal range but still show signs of hyperadrenocorticism. In these cases, the dose should be divided and given twice daily and then adjusted based on subsequent ACTH stimulation test results. One recent report indicated that routine twice daily therapy achieved acceptable control of the hyperadrenocorticism with a lower total daily dose, but more work is needed to clarify this issue.14


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Source: VETERINARY MEDICINE,
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