Low-Dose, Twice-Daily Trilostane Treatment for Dogs with Hyperadrenocorticism

Evaluation of Twice-Daily Lower-Dose Trilostane Treatment Administered Orally in Dogs with Naturally Occurring Hyperadrenocorticism

Edward C. Feldman

Journal of the American Veterinary Medical Association 2011;238:1441–1451.

Since first approved for use in dogs by the FDA in 2009, trilostane (Vetoryl) has become a popular drug commonly used for treatment of dogs with hyperadrenocorticism (Cushing’s syndrome) (1,2). Trilostane is a synthetic nonhormonal steroid analog that acts to inhibit the adrenocortical enzyme 3-beta-hydroxysteroid dehydrogenase, as well as 11-beta hydroylase. By blocking these adrenocortical enzymes, trilostane acts to actively interfere with the adrenal’s metabolic pathways and decreases the synthesis of the adrenal end products, including both cortisol and aldosterone (1-3).

Currently, the initial dosage of trilostane recommended by the manufacturer ranges 2.2-6.7 mg/kg, given orally once each day. However, it is clear that the duration of adrenal inhibition in most dogs is much less than 24 hours (1,4,5), and a number of adverse reactions can develop secondary to the drug, especially if higher doses are given (6-12).

Because it is known that trilostane generally has a duration of effect that is less than 24 hours, further investigation of a twice daily dosing regimen is warranted. Dividing the daily dose into twice daily administration might also help lower the prevalence of adverse effects associated with the drug. The purpose of this current study by Feldman (13) was to carefully evaluate the effects of twice-daily, lower-dose trilostane treatment administered to dogs with naturally occurring Cushing’s syndrome.

Objective—To evaluate effectiveness and incidence of adverse reactions to twice-daily lower-dose oral administration of trilostane in the treatment of dogs with naturally occurring hyperadrenocorticism.

Design—Clinical trial.

Animals—47 dogs with naturally occurring hyperadrenocorticism.

Procedures—47 dogs were treated orally with trilostane (0.21 to 1.1 mg/kg, q 12 h). All dogs were reevaluated at 2 weeks and 2 months, 38 dogs at 6 months, and 28 dogs at 1 year of treatment.

Results—9 of 47 dogs had an adrenocortical tumor causing hyperadrenocorticism, and all had good responses after 2 months (mean trilostane dosage, 0.89 mg/kg, q 12 h). All successfully underwent surgical adrenal tumor extirpation.

Thirty-eight dogs had pituitary-dependent hyperadrenocorticism (PDH); 15 dogs did not require a dose increase during the study, and at each of 4 reevaluations, 10 of 15, 13 of 15, 14 of 15, and 11 of 11 had a good response. Twenty-three dogs with PDH had their dose or frequency of trilostane administration increased during the study.

Mean trilostane dosage at 1-year reevaluation in dogs with a good response was 1.7 mg/kg (0.8 mg/lb), twice daily, or 1.1 mg/kg, 3 times daily. At each of 4 reevaluations, 17 of 23, 14 of 23, 17 of 23, and 13 of 17 dogs with PDH had a good response. Five dogs became ill because of trilostane-induced adverse effects, but only 1 required hospitalization.

Conclusions and Clinical Relevance—Administration of initial lower doses of trilostane to dogs with hyperadrenocorticism is effective.

Bottom Line: 

Initial daily dosage of trilostane
When this drug was first used in Europe over a decade ago, the original starting dose was 4-10 mg/kg/day (7-12). However, as experience with the drug grew, it became apparent that these doses were too high in many dogs and lower doses were needed. Accordingly, the dosing recommendation on the US package insert states that an initial daily dose of 2.2-6.7 mg/kg is recommended (4).

My recommended starting dose is either 2 mg/kg given once daily or 1 mg/kg given twice daily. This is similar to the doses used in this study by Feldman (13), where the mean trilostane dose administered to his dogs was 0.86 mg/kg, twice daily (or a mean total daily dose of 1.72 mg/kg). Like Feldman, I feel that it is best to start with a daily dose that is at the low end or even lower than that recommended in the package insert.  I would never start a dog on a dose at the higher end of the recommended dosage range (4-7 mg/kg), although some dogs with Cushing’s disease will eventually require daily doses that may be this high or even higher (1,14).

SID, BID, or TID administration?
Whether to start with once- or twice-daily trilostane administration is controversial (1,2). Although most dogs are controlled clinically with once-daily dosing, trilostane may begin to lose its effectiveness 8-10 hours after administration, so twice daily dosing may be necessary in a subset of dogs (1,4).

In addition, it is very possible that the efficacy of twice-daily dosing might be more effective than once-daily dosing in controlling the complications of Cushing’s syndrome (e.g., proteinuria or hypertension). However, the answer that question remains unclear (15), and additional studies are needed to resolve that issue.

So what do I recommend? Until it is proven that SID or BID treatment is better, I prefer to start with a twice-daily regimen —if feasible and the owner agrees —because controlling cortisol concentrations throughout as much of the day as possible makes sense to me. In diabetic dogs with concurrent Cushing’s disease, twice-daily administration is essential in avoiding large fluctuations in serum cortisol concentrations during the day (1,2). With once-daily trilostane administration, adequate diabetic control will be next to impossible in many dogs with concurrent Cushing's syndrome.

What about TID administration? In this study, 9 (24%) of the 38 dogs with PDH were eventually switched to a regime of trilostane, administered every 8 hours. In my practice, I have not found it necessary to use TID dosing, and I do not find that dose schedule very practical or realistic for most owners.  If I can't remember to "take a pill" every 8 hours (and I can't!), how can we really expect the owners to give their dog a medication three times a day for the rest of their dog's life?

Monitoring & the goals of therapy
We must use a combination of the dog's clinical response and the results of ACTH stimulation testing to monitor dogs on trilostane treatment. In this paper (13), Feldman had three goals of therapy, which included the following:

• a post-ACTH serum cortisol concentration ≤ 5.5 μg/dl (3-4 hours after the morning dose) 
• a urine specific gravity > 1.020 
• owner satisfaction in dog’s improvement.

Of these 3 goals, I agree completely with the last one — the owner's evaluation of the clinical response is key. As far as the urine specific gravity goes, I would agree that most dogs will be able to concentrate their urine to greater than 1.020 once the polyuria resolves. However, if the urine specific gravity is less than 1.020, I would certainly not raise the dose if the owner reported a good clinical response and serum cortisol concentrations were lowered to within the desired range.

Dosage adjustments — raising the dose
In this paper, Feldman recommends that dogs that continue to be symptomatic with a post-ACTH stimulation serum cortisol concentration > 5.5 μg/dl should have the daily dose of trilostane increased. I agree with that recommendation. However, the 5.5 μg/dl cutoff value used in his study was not very sensitive — 40 of the 122 dogs (or a third of cases of this report) with a good clinical response to trilostane had a post-ACTH serum cortisol concentrations higher than 5.5 μg/dl.

For my cases, I recommend maintaining a post-ACTH cortisol concentration between 2-7 μg/dl when tested 4-5 hours after the morning dose. So for a dog that was clinically improved but has a post-ACTH cortisol above 5.5 μg/dl but  below 7.0 μg/dl, I would not recommend increasing the dose in those dogs. Many of those dogs will go on for months on the same dosage, without the need for a higher dose.

Dosage adjustments — lowering the dose
In this report (13), trilostane treatment was continued in dogs with a post-ACTH cortisol concentration less than 1.5 μg/dl, as long as no adverse clinical signs were reported. I disagree with that regime.

When using trilostane, it has become increasing clear that we do not want the cortisol values to drop too low, because that may indicate early or mild adrenal necrosis (1,11,12). In contrast to the protocol used in this reported study, I recommend stopping the drug in all dogs that develop a ACTH-stimulated cortisol values less than 2.0 μg/dl, and repeating the ACTH stimulation test in 1- to 2-weeks in those dogs. Some of these dogs will require that the drug be restarted at a lower dosage, but others will maintain low to normal serum cortisol concentrations for prolonged periods of time. And a subset of these dogs, presumably because of mild adrenal necrosis, will never need any further trilostane treatment to control the signs of Cushing's syndrome.

References:

1. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
2. Ramsey IK. Trilostane in dogs. Vet Clin North Am Small Anim Pract 2010;40:269-283. 
3. Wenger M, Sieber-Ruckstuhl NS, Muller C, et al. Effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 2004;65:1245-1250. 
4. Dechra Veterinary Products, U.S. Website. Vetoryl package insert. Overland Park, Kan: Dechra Veterinary Products, 2008.
5. Alenza DP, Arenas C, Lopez ML, et al. Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism. J Am Anim Hosp Assoc 2006;42:269-276. 
6. Vaughan MA, Feldman EC, Hoar BR, et al. Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2008;232:1321-1328. 
7. Neiger R, Ramsey I, O'Connor J, et al. Trilostane treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. Vet Rec 2002;150:799-804. 
8. Ruckstuhl NS, Nett CS, Reusch CE. Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Am J Vet Res 2002;63:506-512.
9. Braddock JA, Church DB, Robertson ID, et al. Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. Aust Vet J 2003;81:600-607. 
10. Bell R, Neiger R, McGrotty Y, et al. Study of the effects of once daily doses of trilostane on cortisol concentrations and responsiveness to adrenocorticotrophic hormone in hyperadrenocorticoid dogs. Vet Rec 2006;159:277-281. 
11. Chapman PS, Kelly DF, Archer J, et al. Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism. J Small Anim Pract 2004;45:307-310. 
12. Ramsey IK, Richardson J, Lenard Z, et al. Persistent isolated hypocortisolism following brief treatment with trilostane. Aust Vet J 2008;86:491-495. 
13. Feldman EC. Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2011;238:1441-1451. 
14. Feldman EC, Kass PH. Trilostane dose versus body weight in the treatment of naturally occurring pituitary-dependent hyperadrenocorticism in dogs. J Vet Intern Med 2012;26:1078-1080. 
15. Smets PM, Lefebvre HP, Meij BP, et al. Long-term follow-up of renal function in dogs after treatment for ACTH-dependent hyperadrenocorticism. J Vet Intern Med 2012;26:565-574.