Trilostane

Adrenal steroidogenesis inhibitor Synthetic steroid analogue

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO Initial: 1-3 mg/kg once daily; adjust based on response. For twice-daily dosing, use 1-2 mg/kg every 12 hours. Once daily (or divided twice daily in some cases) Duration: Long-term; adjust dose based on clinical response and ACTH stimulation test results.
Notes: Administer with food. Re-evaluate at 10-14 days, then at 30 days, and every 3-6 months thereafter. Dose adjustments should be based on clinical signs and ACTH stimulation test (post-ACTH cortisol should be 2-5 µg/dL).
Cat PO 2-3 mg/kg once daily (off-label) Once daily Duration: Long-term; monitor closely.
Notes: Limited evidence; use cautiously. Monitor electrolytes and renal function.

Clinical Indications & Species Uses

General Indications
  • Treatment of hyperadrenocorticism (Cushing's syndrome) in dogs
Dog (Canine)
  • Pituitary-dependent hyperadrenocorticism (PDH)
  • Adrenal-dependent hyperadrenocorticism (ADH) due to adrenal tumor
  • Hyperadrenocorticism (Cushing's syndrome) for medical management
Cat (Feline)
  • May be used off-label for feline Cushing's syndrome

Pharmacology & Mechanism of Action

Drug Class: Adrenal steroidogenesis inhibitor | Pharmacological Group: Synthetic steroid analogue

Mechanism of Action: Trilostane is a competitive inhibitor of the 3β-hydroxysteroid dehydrogenase enzyme system, which is essential for the synthesis of glucocorticoids, mineralocorticoids, and androgens in the adrenal cortex. By inhibiting this enzyme, trilostane reduces the production of cortisol and other steroids, thereby controlling the clinical signs associated with hyperadrenocorticism (Cushing's syndrome). It has minimal effect on aldosterone at therapeutic doses, but at higher doses can reduce aldosterone production, leading to electrolyte imbalances.

Pharmacodynamics: Trilostane produces a dose-dependent suppression of cortisol production. It is rapidly acting, with peak effect occurring within 1-2 hours after oral administration. The duration of action is approximately 8-12 hours, making it suitable for twice-daily dosing in some cases. It does not have direct anti-inflammatory or immunosuppressive effects; its effects are mediated through reduction of cortisol levels. Chronic therapy leads to normalization of adrenal function and clinical improvement in signs of hyperadrenocorticism.

⚡ Pharmacokinetics Summary

Absorption: Trilostane is well absorbed after oral administration in dogs, with peak plasma concentrations occurring within 1.5-2 hours. Food can increase absorption, so it is recommended to administer with food to enhance bioavailability.
Distribution: Trilostane is widely distributed in tissues. It crosses the blood-brain barrier to a limited extent. It is extensively metabolized in the liver, and its metabolites are excreted in urine and feces.
Metabolism: Trilostane undergoes extensive hepatic metabolism, primarily to its active metabolite, ketotrilostane, which also has inhibitory activity. The metabolism involves reduction and conjugation reactions.
Excretion: Trilostane and its metabolites are excreted primarily in the urine (approximately 70%) and feces (approximately 30%). In dogs, the elimination half-life is short, approximately 1-2 hours for the parent drug, but the active metabolite may have a longer half-life.
Half-Life: Dogs: 1-2 hours (parent drug); active metabolite may have longer half-life.
Bioavailability: Oral bioavailability is approximately 70-90% in dogs when administered with food.
Protein Binding: Trilostane is moderately protein-bound (approximately 70-80%) in dogs.

Available Formulations & Strengths

Capsule 5 mg, 10 mg, 30 mg, 60 mg, 120 mg (PO)
Oral suspension (compounded) Various (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to trilostane or any component of the formulation
  • Hepatic dysfunction (severe)
  • Renal insufficiency (severe)
  • Primary hepatic disease
  • Pregnancy or lactation (unless benefits outweigh risks)
  • Concurrent use with mitotane (potential for severe adrenal necrosis)
Warnings & Clinical Precautions:
  • Use with caution in animals with pre-existing renal or hepatic disease.
  • Monitor for signs of hypoadrenocorticism (Addisonian crisis) such as lethargy, vomiting, diarrhea, collapse, or electrolyte imbalances.
  • May cause a transient increase in liver enzymes; monitor liver function periodically.
  • Do not use in animals with primary hepatic disease or renal insufficiency.
  • Safety in breeding, pregnant, or lactating animals has not been established.
  • Use with caution in animals receiving potassium-sparing diuretics or ACE inhibitors due to risk of hyperkalemia.
  • Monitor body weight, appetite, and water intake regularly.
  • ACTH stimulation tests should be performed to guide dosing and monitor therapy.
  • If signs of hypoadrenocorticism occur, discontinue trilostane and administer glucocorticoids and mineralocorticoids as needed.

Adverse Effects & Reactions

Common:

  • Vomiting
  • Diarrhea
  • Lethargy
  • Decreased appetite
  • Weakness
  • Elevated liver enzymes (ALT, ALP)

Serious / Severe:

  • Hypoadrenocorticism (Addisonian crisis)
  • Hyperkalemia
  • Hyponatremia
  • Acute renal failure
  • Hepatic necrosis
  • Adrenal necrosis
  • Gastrointestinal ulceration
  • Death (rare)

Rare:

  • Cutaneous reactions
  • Blood dyscrasias
  • Neurological signs (ataxia, tremors)
  • Pancreatitis

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Potassium-sparing diuretics (e.g., spironolactone) Additive hyperkalemia; monitor potassium levels. High
ACE inhibitors (e.g., enalapril) Increased risk of hyperkalemia and hypotension. Moderate
NSAIDs (e.g., carprofen) Increased risk of gastrointestinal ulceration and renal toxicity. Moderate
Corticosteroids (e.g., prednisone) May antagonize the effects of trilostane; monitor response. Moderate
Mitotane Severe adrenal necrosis; avoid concurrent use. High
Phenobarbital May increase metabolism of trilostane, reducing efficacy. Mild

Overdose & Toxicity Management

Signs of Toxicity:

  • Vomiting
  • Diarrhea
  • Lethargy
  • Weakness
  • Collapse
  • Hypotension
  • Hyperkalemia
  • Hyponatremia
  • Acute adrenal insufficiency
  • Renal failure

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce emesis if recent ingestion. Administer activated charcoal to reduce absorption. Provide intravenous fluids with electrolyte replacement. Administer glucocorticoids (e.g., prednisolone) and mineralocorticoids (e.g., fludrocortisone) if adrenal insufficiency occurs. Monitor electrolytes, renal function, and vital signs. In severe cases, hospitalization and intensive care may be required.

Food Animal Withdrawal Times

Not approved for use in food animals. Withdrawal times not established. Do not use in animals intended for food production.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature 20-25°C (68-77°F), excursions permitted between 15-30°C (59-86°F).

Handling & Special Conditions: Protect from moisture. Keep container tightly closed. Compounded suspensions should be stored according to pharmacy instructions, typically refrigerated and used within a specified period.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: FDA-approved for use in dogs (Vetoryl).

Extra-Label (Off-Label) Use: In the US, trilostane is FDA-approved for use in dogs. Extra-label use in other species is permitted under AMDUCA with appropriate veterinary oversight, but withdrawal times and safety in food animals are not established. In the EU, trilostane is approved for dogs; use in other species is off-label.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Trilostane is the preferred medical treatment for canine hyperadrenocorticism due to its efficacy and safety profile. It is important to individualize dosing based on clinical response and ACTH stimulation test results. The goal is to achieve a post-ACTH cortisol concentration of 2-5 µg/dL. Monitor for signs of hypoadrenocorticism, especially during the initial weeks of therapy. Adjust dose as needed; some dogs may require twice-daily dosing. In cats, use is limited and should be done with caution. Always administer with food to enhance absorption. Educate owners on the signs of adverse effects and the importance of regular monitoring. For animals with concurrent diseases, such as diabetes mellitus or urinary tract infections, manage appropriately. Avoid use in pregnant or lactating animals due to lack of safety data. Regular monitoring of electrolytes, renal function, and liver enzymes is recommended.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)