Read the German translation: Trilostan--Übersicht über eine Erfolgsgeschichte

Introduction

In dogs with hyperadrenocorticism (HAC) the method of treatment should be carefully chosen based on the cause (pituitary-dependent HAC, PDH or adrenocortical tumor HAC, ATH) of disease, age and condition of the patient and presence of concomitant disease. Cost and availability of treatment methods as well as frequency of follow-up evaluations are also important considerations.

In case of ATH surgical removal is in principle the treatment of choice. However, since adrenalectomy is technically challenging and frequently associated with postoperative complications medical treatment is often used instead. In people with PDH transsphenoidal pituitary surgery has become the treatment of choice. In dogs hypophysectomy is only rarely performed, it is currently possible only in very few specialized veterinary centers and requires a team approach, involving a neurosurgeon, an endocrinologist and a radiologist. Transsphenoidal hypophysectomy however, has the potential to become the treatment of choice for dogs (and cats) with PDH.

The standard medical treatment for HAC (PDH and ATH) dogs has long been mitotane. Mitotane leads to selective, progressive necrosis of the adrenal cortex, which may be partially or completely destroyed, depending on the treatment protocol. The efficacy of mitotane is favourable and more than 80% of dogs with PDH have a good to excellent response. Disadvantages of mitotane include potential development of adrenocortical insufficiency, possible drug intolerance, and a relatively high frequency of relapses during therapy. Due to these problems a variety of other drugs has been investigated, most of which have limited efficacy.

The investigation of trilostane, however, has lead to a true success story. The first report of the use of trilostane was by Hurley et al in 1998 who successfully treated 13 dogs with PDH and 2 with ATH.¹ Since then the drug has gained wide popularity, especially in Europe. While initially the human preparation was used (Modrenal®), trilostane is now officially registered for use in dogs under the name of Vetoryl® in many countries.

Mode of Action and Pharmacology

From studies in humans and various other species it is known that trilostane is a competitive inhibitor of 3β-hydroxysteroid-dehydrogenase. This enzyme system mediates the conversion of pregnenolone to progesterone in the adrenal gland. Cortisol, aldosterone and androstenedione are produced from progesterone via various biochemical pathways. Since trilostane inhibits progesterone synthesis it blocks the synthesis of its end products. Recently, it was shown that also in dogs, trilostane has an inhibitory effect on the 3β-hydroxysteroid dehydrogenase enzyme system. However, this inhibition does not seem to be its only effect. There is an additional effect more distal in the enzyme cascade and possibly also on the interconversion of cortisol to cortisone.^2,3

Various studies have shown that treatment with trilostane induces a significant decrease of the basal and ACTH-stimulated cortisol concentration.^4,5,6 As a result there is a loss of negative feedback leading to an increase in endogenous ACTH.^2,7

Trilostane not only influences the pituitary-adrenal gland axis but also the renin-aldosterone axis. In line with his inhibitory effect on 3β-HSD trilostane lowers the aldosterone concentration, although the decrease is considerably less than that of cortisol.⁸ The decline, however, is sufficient to induce an increase in renin activity.⁹

After oral dosing trilostane is rapidly absorbed and peak concentrations are seen in healthy dogs after 1.5-2 hours. Concentrations return to baseline levels after 10-18 hours. There is substantial variability in plasma levels of trilostane which may be due to low water solubility and erratic absorption. Feeding increases the absorption of the drug.

Use in Canine PDH

Trilostane has been evaluated in several clinical studies from centres in Europe and the US including a total of 244 dogs.^{4,5,6,9,10,11} Direct comparison is difficult because starting dosages, monitoring protocols and dose adjustments varied, however, they all came to the conclusion that trilostane is an efficacious and safe drug. In Zurich we are using trilostane since 1999 and in dogs with PDH it has replaced the use of mitotane completely. In our first study in 2002 we found that 82% of dogs with PDH had resolution of clinical signs and the remaining dogs showed marked clinical improvement.⁵ The success rate has been similar in the following years, 80-90% of dogs with PDH show a good to excellent response. In the other studies clinical efficacy was 67%, 77%, 89%, 95% and 100%.

The time required for a noticeable improvement is similar to that of mitotane. There is a rapid decrease in polydipsia, and polyuria, and an increase in activity level and a delayed improvement (weeks to months) in hair coat and skin condition and abdominal muscle tone. Polyphagia often persists or decreases only marginally. Some dogs may have transient worsening of their dermatologic problems before clinical improvement.

Starting Dose and Monitoring

Initially only 60 mg capsules were available rendering dosing per kg bodyweight impossible. Dose therefore was determined on the basis of 3 categories of bodyweight: dogs less than 5 kg received 30 mg SID (1/2 capsule), dogs 5 to 20 kg received 60 mg SID (1 capsule) and dogs greater than 20 kg 120 mg SID (2 capsules). Today 10 mg, 30 mg, 60 mg and 120 mg capsules are available. The recommended starting dose, although slightly altered by the company (in particular for small dogs), is still according to weight categories. Re-evaluations and dose adjustments have to be performed frequently initially, after several months dose becomes relatively stable in the majority of cases.

According to a recent consensus statement of endocrinologists of seven European countries (Amsterdam, 19.4.2006) initial dose should be according to bodyweight and should be in the range of 2-5 mg/kg (in dogs < 10 kg at the lower end of the dose range). Applications should be SID, in the morning with food. Re-evaluations should be performed after 1-2 weeks, 4 weeks, 12 weeks and then every 3 months. They should include history, physical examination, the most important blood parameters (kidney parameters, liver enzymes, electrolytes) and an ACTH stimulation test. The latter test determines adrenal reserve and is therefore suitable for evaluating the extent of enzyme inhibition during treatment and for calculating dosage adjustments. It is important that testing is performed always at the same time. According to the consensus statement it should be performed 2 to 3 hours after drug administration, which corresponds to the peak effect of trilostane. The target range of the post ACTH cortisol level at 2-3 hours post pill should be 40 to 150 nmol/l (1.4-5.4 µg/dl). The urinary corticoid: creatinine ratio cannot be used as an alternative to the ACTH test to determine the optimal dose of trilostane.¹² Adjustments of trilostane dose should be made in increments of 10 to 30 mg/dog. The effective dosage of trilostane differs markedly among dogs with PDH which may be due to variation in 3β-hydroxysteroid dehydrogenase activity in adrenal glands, variable absorption or variable conversion into active metabolites such as ketotrilostane.

Since the effect of trilostane is short lasting BID application has been proposed by some authors.^10,11 However, the overall results do not appear to be superior to SID application.

Side Effects and Survival

Trilostane is well tolerated by most dogs. Adverse effects are seen in 10-25% of dogs and may be due to a direct drug effect, glucocorticoid withdrawal or hypoadrenocorticism. In case of direct drug effect or glucocorticoid withdrawal severity is usually mild and signs may be self-limiting, hypoadrenocorticism, however, may cause serious signs. In case of adverse effects it is advisable to perform an ACTH stimulation test to exclude hypoadrenocorticism. While awaiting the results trilostane administration should be stopped and symptomatic treatment (IV fluids, glucocorticoids) considered. After recovery trilostane should be restarted at a lower dose.

A small percentage of dogs will develop permanent or long lasting hypoadrenocorticism requiring mineralocorticoid and glucocorticoid supplementation. This phenomenon may be due to adrenal necrosis which has been described in 2 case reports and a case series with 7 dogs, 6 of which had adrenal necrosis and/or apoptosis.^13,14,15 Adrenal necrosis cannot be explained with the current knowledge about the actions of trilostane. According to preliminary results of an experimental study we assume that it is caused by the increasing level of endogenous ACTH.¹⁶ This would fit with a very recent assumption that finding an increased ACTH level may be helpful to detect trilostane overdosage.⁹

Survival times were investigated in 2 studies and found to be 662 days (median) and 930 days (mean).^10,17

Use in Canine ATH and in Feline HAC

According to a small number of published cases and our own experience trilostane appears to work in dogs with ATH.^18,19 We are currently using the same treatment protocol as for dogs with PDH. Trilostane leads to some clinical improvement in cats with HAC, and although data are scarce it may be the drug of choice. Initial dosage usually is 30 mg/cat SID.^20,21

References

1.  Hurley K, et al. JVIM 1998;12:210.

2.  Sieber-Ruckstuhl N, et al. Dom Anim Endocrinol 2006;31:63.

3.  Sieber-Ruckstuhl N, et al. Vet Rec 2008;163:477.

4.  Neiger R, et al. Vet Rec 2002;150:799.

5.  Ruckstuhl N, et al. AJVR 2002;63:506.

6.  Braddock JA, et al. Aust Vet J 2003;81:600.

7.  Witt AL, Neiger R. Vet Rec 2003;154:399.

8.  Wenger M, et al. AJVR 2004;65:1245.

9.  Galac S, et al. Vet J 2010;183:75.

10. Alenza DP, et al. JAAHA 2006;42:269.

11. Vaughan MA, et al. JAVMA 2008;232:1321.

12. Galac S, et al. JVIM 2009;23:1214.

13. Chapman PS, et al. JSAP 2004;45:307.

14. Reusch CE, et al. Vet Rec 2007;160:219.

15. Ramsey IK, et al. Aust Vet J 2008;86:491.

16. Burkhardt W, et al. ECVIM-CA congress 2009.

17. Barker EN, et al. JVIM 2005;19:810.

18. Eastwood JM, et al. JSAP 2003;444:126.

19. Benchekroun G, et al. Vet Rec 2008;163:190.

20. Skelly BJ, et al. JSAP 2003; 44:269.

21. Neiger R, et al. JVIM 2004;18:160.