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Update on the Use of Trilostane

Ellen Behrend, VMD, PhD, Diplomate ACVIM, Auburn University

Endocrinology & Metabolic Diseases

|June 2011|Peer Reviewed

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You have asked…How is trilostane currently used to treat PDH in dogs?

The expert says…

As a synthetic steroid analog that inhibits the adrenocortical enzyme 3-beta-hydroxysteroid dehydrogenase, trilostane (Vetoryl, dechra.com) suppresses production of progesterone and its end products, including cortisol and aldosterone. Additional enzymes such as 11-beta-hydroxylase and 11-beta-hydroxysteroid dehydrogenase may also be affected.1 Trilostane is approved by the U.S. Food and Drug Administration (FDA) for the treatment of canine hyperadrenocorticism.

Overall, trilostane is highly effective in suppressing cortisol secretion and controlling clinical signs in dogs with pituitary-dependent hyperadrenocorticism (PDH).2-8 Clinical signs typically resolve quickly with control of cortisol concentrations, but some abnormalities, including dermatologic manifestations, can take up to 3 months, and others, such as calcinosis cutis, may never fully resolve. A small proportion of dogs with PDH are not well controlled with trilostane.5,8,9

The doses and warnings associated with trilostane treatment of PDH have changed over time. Some areas are still controversial.

Related Article: Atypical Hyperadrenocorticism in a Dog

Dose
Originally, the recommended starting dose for trilostane in Europe was 2 to 10 mg/kg Q 24 H. However, as experience with the drug grew, it became apparent that lower doses were needed. Accordingly, the dosing recommendation on the U.S. package insert is 2.2 to 6.7 mg/kg Q 24 H.

Whether to start with once- or twice-daily administration is controversial. Although most dogs are controlled clinically with once-daily dosing (ie, clinical signs apparent to the owner resolve), trilostane may begin losing effectiveness 8 to 10 hours after administration,2,10,11 so twice daily dosing may be necessary.2-4 In addition, the efficacy of once-daily dosing in controlling all complications of PDH, such as proteinuria or hypertension, is unknown.
 
My recommended starting dose is either 2 mg/kg Q 24 H or 1 mg/kg Q 12 H, with adjustments made as needed based on adrenocorticotropic hormone (ACTH) stimulation testing. Until it is proven which treatment approach is better, I prefer to start with a twice-daily regimen if the owner agrees because controlling cortisol concentration throughout as much of the day as possible makes sense. In diabetic patients with hyperadrenocorticism, twice-daily dosing is absolutely recommended to avoid large fluctuations in serum cortisol concentrations. In approximately 50% of dogs, dose adjustments, either up or down, are required during treatment. The authors of one study noted that in most dogs an initial sensitivity to the drug existed, followed by a need for a dose increase. After time, the dose required often reached a plateau.5

Related Article: Cutaneous Manifestations of Canine Hyperadrenocorticism—Exogenous or Endogenous

Timing Postpill Monitoring
An ACTH stimulation test must be conducted to evaluate therapy. However, the optimal post-ACTH serum cortisol concentration and timing of sampling remain to be elucidated. Cortisol concentrations may vary with the interval between dosing and testing.10 In accordance with the package insert, I recommend starting the ACTH stimulation test 4 to 6 hours after administration. It is helpful to time postpill ACTH testing consistently.

Other timing strategies have been reported but are not currently recommended. Baseline cortisol concentration has been evaluated as a monitoring tool12; however, because the clinical status of the study dogs was not reported, the results are difficult to interpret. In addition, baseline cortisol concentration was deemed adequate only for dogs doing well clinically and whose basal concentration fell within a narrow range. For twice-daily therapy, although one study suggested starting the test 8 to 12 hours after dosing,4 such timing has not been critically evaluated.

Timing Dose Adjustments
Once trilostane therapy has been initiated, a recheck should be performed at 10 to 14 days or sooner if needed. Recommendations for when to alter dose have become less stringent. The dose should be raised at the first recheck only if the owner reports no improvement, clinical signs are still striking, and the post-ACTH cortisol concentration is markedly above ideal. If any improvement is noted, the dose should remain the same as long as cortisol concentrations are within the ideal range or higher. Current impression is that basal and ACTH-stimulated cortisol concentrations continue to decrease until the 4-week recheck even if the same trilostane dose is administered. If the basal or ACTH-stimulated cortisol concentrations are below ideal at any time, trilostane administration should be discontinued temporarily and the dose decreased when resumed. If no adjustment was made at the first recheck, a second recheck should be done at about day 30 after initiating trilostane administration. Future rechecks are based on the dog’s clinical progress, previous ACTH stimulation test results, and whether dose adjustment was needed.

Safety
A majority of reported adverse effects, including lethargy and vomiting, are relatively mild, but fatalities have occurred.5,8,9 Although some studies reported a relatively low incidence of side effects, one non–peer-reviewed report states mild, self-limiting side effects such as diarrhea, vomiting, and lethargy occur in 63% of treated dogs.14 Since the clinical signs of drug toxicity and hypocortisolemia are the same, an ACTH stimulation test is usually required to differentiate them.

As with mitotane therapy, excess adrenal gland suppression can occur and warrants discontinuing trilostane administration temporarily. Although in theory the effects of trilostane as an enzyme inhibitor should be rapidly reversible (ie, within a couple days), suppression can last weeks to years.4,5,15,16 With oversuppression, recommendations from many sources are to simply discontinue the medication for a few days and then begin again at a reduced dose. I prefer to perform an ACTH stimulation test to document return of function first. One dog developed hypocortisolism after only 3 doses of trilostane and it lasted at least 1 year.15

Adrenal necrosis can occur secondary to trilostane administration.17 The hypoadrenocorticism reported after complete adrenocortical necrosis in one dog lasted at least 3 months but likely would be permanent. How often acute iatrogenic hypoadrenocorticism will occur with trilostane is unknown but is likely more common than originally believed. In one study, 4 of 6 dogs with PDH and 1 dog with adrenal tumor treated with trilostane had some degree of adrenal necrosis at necropsy.

Text at a Glance:

  • Starting dose of trilostane for PDH treatment:
    • 2 mg/kg Q 24 H or
    • 1 mg/kg Q 12 H
  • Q 12 H administration is preferred if the owner will comply but is absolutely recommended for diabetic dogs to stabilize serum cortisol concentration.
  • Recheck at 10 to 14 days or sooner if adverse events are noted; if any improvement occurs, the dose should not be changed if the cortisol concentrations are ideal or above.
  • If no adjustment is made at the first recheck, recheck at about day 30 after initiating trilostane administration, as dose adjustments are generally needed.
  • The need for future rechecks is based on clinical progress, previous test results, and whether a dose adjustment was needed.

UCCR & Monitoring

  • An early study found that the urine cortisol:creatinine ratio (UCCR) before administering trilostane could be an indication of duration of action, but 2 later studies yielded conflicting results.2,5,13
  • Interestingly, in one report of 6 dogs that had UCCRs within the reference range “most of the time,” 3 developed hypocortisolism (Addison's disease) and hypocortisolism was suspected but not confirmed in the other 3 dogs.13

Further research is needed to determine whether UCCR will prove useful as a monitoring tool.

ACTH = adrenocorticotropic hormone, PDH = pituitary-dependent hyperadrenocorticism, UCCR = urine cortisol:creatinine ratio

For additional information about canine PDH, see Do These Dogs Have Cushing’s Disease? & Low-Dose Dexamethasone Suppression Testing for Hyperadrenocorticism


UPDATE ON THE USE OF TRILOSTANE • Ellen Behrend

References

1. Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrations in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Sieber-Ruckstuhl NS, Boretti FS, Wenger M, et al. Domest Anim Endocrinol 31:63-75, 2006.
2. Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. Vaughn MA, Feldman EC, Hoar BR, Nelson RW. JAVMA 232:1321-1328, 2008.
3. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Clemente M, De Andres PJ, De Arenas C, et al. Vet Rec 161:805-809, 2007.
4. Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism. Alenza DP, Arenas C, Lopez ML, Melian C. JAAHA 42:269-276, 2006.
5. Trilostane treatment in dogs with pituitarydependent hyperadrenocorticism. Braddock JA, Church DB, Robertson ID, Watson ADJ. Austral Vet J 81:600-607, 2003.
6. A comparison of the survival times of dogs treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism. Barker EN, Campbell S, Tebb AJ, et al. J Vet Intern Med 19:810-815, 2005.
7. Trilostane treatment of 78 dogs with pituitarydependent hyperadrenocorticism. Neiger R, Ramsey IK, O’Conner J, et al. Vet Rec 150:799-804, 2002.
8. Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Ruckstuhl NS, Nett CS, Reusch C. Am J Vet Res 63:506-512, 2002.
9. Trilostane therapy of canine hyperadrenocorticism. Neiger R, Ramsey IK. Proc 20th Annu ACVIM Forum:544-546, 2002.
10. Adrenocorticotropic hormone levels in dogs with pituitary-dependent hyperadrenocorticism following trilostane therapy. Witt A, Neiger R. Vet Rec 154:399-400, 2004.
11. Study of the effects of once daily doses of trilostane on cortisol concentrations and responsiveness to adrenocorticotrophic hormone in hyperadrenocorticoid dogs. Bell R, Neiger R, McGrotty Y, Ramsey IK. Vet Rec 159:277-281, 2006.
12. Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism. Cook AK, Bond KG. JAVMA 237:801-805, 2010.
13. Urinary corticoid:creatinine ratios in dogs with pituitary-dependent hypercortisolism during trilostane treatment. Galac S, Buijtels JJCWM, Kooistra HS. J Vet Intern Med 23:1214-1219, 2009.
14. Hyperadrenocorticism: The animal perspective—Comparative efficacy and safety of trilostane. Neiger R. Proc 22nd Annu ACVIM Forum:699-701, 2004.
15. Persistent isolated hypocortisolism following brief treatment with trilostane. Ramsey IK, Richardson J, Lenard Z, et al. Austral Vet J 86:491-495, 2008.
16. Effects of trilostane on the pituitary-adrenocortical and renin-aldosterone axis in dogs with pituitary-dependent hypercortisolism. Galac S, Buijtels JJCWM, Mol JA, Kooistra HS. Vet J 183:75-80, 2010.
17. Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism. Chapman PS, Kelly DF, Archer J, et al. J Small Anim Pract 45:307-310, 2004.

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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