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Trilostane
Trilostane
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Trilostane
Clinical data
Trade namesVetoryl, others
Other namesWIN-24,540; 4α,5-Epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile
Routes of
administration		By mouth[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver
Metabolites17-Ketotrilostane[1]
Elimination half-lifeTrilostane: 1.2 hours[1]
17-Ketotrilostane: 1.2 hours[1]
Identifiers
  • (1S,2R,6R,8S,11S,12S,15S,16S)-5,15-dihydroxy-2,16-dimethyl-7-oxapentacyclo[9.7.0.02,8.06,8.012,16]octadec-4-ene-4-carbonitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.033.743 Edit this at Wikidata
Chemical and physical data
FormulaC20H27NO3
Molar mass329.440 g·mol−1
3D model (JSmol)
  • N#C\C4=C(/O)[C@H]5O[C@]35[C@]([C@@H]2[C@H]([C@H]1[C@]([C@@H](O)CC1)(C)CC2)CC3)(C)C4
  • InChI=1S/C20H27NO3/c1-18-7-6-14-12(13(18)3-4-15(18)22)5-8-20-17(24-20)16(23)11(10-21)9-19(14,20)2/h12-15,17,22-23H,3-9H2,1-2H3/t12-,13-,14-,15-,17+,18-,19+,20+/m0/s1 checkY
  • Key:KVJXBPDAXMEYOA-CXANFOAXSA-N checkY
  (verify)

Trilostane, sold under the brand name Vetoryl among others, is a medication which has been used in the treatment of Cushing's syndrome, Conn's syndrome, and postmenopausal breast cancer in humans.[6][7][8][9][1] It was withdrawn for use in humans in the United States in the 1990s[10] but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing's syndrome in dogs.[11] It is taken by mouth.[1]

Medical uses

[edit]

Trilostane has been used in the treatment of Cushing's syndrome (hypercortisolism), Conn's syndrome (hyperaldosteronism), and postmenopausal breast cancer in humans.[7][1] When used to treat breast cancer, trilostane is administered in combination with a corticosteroid to prevent glucocorticoid deficiency.[1]

Contraindications

[edit]

Trilostane should not be used in pregnant women.[1]

Trilostane should not be given to a dog that:

Side effects

[edit]

Side effects of trilostane in conjunction with a corticosteroid in humans include gastrointestinal side effects like gastritis, nausea, vomiting, and diarrhea.[1] Nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of diarrhea with trilostane.[1] Serious gastrointestinal side effects of trilostane alone or in combination with an NSAID like peptic ulcer, erosive gastritis, gastric perforation, hematemesis, and melena may occur in some individuals.[1] Reversible granulocytopenia and transient oral paresthesia may occur with trilostane.[1]

Pharmacology

[edit]

Pharmacodynamics

[edit]
Steroidogenesis. Trilostane inhibits 3β-HSD.

Trilostane is a steroidogenesis inhibitor.[1] It is specifically an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD).[1][15] As a result of this action, trilostane blocks the conversion of Δ5-3β-hydroxysteroids, including pregnenolone, 17α-hydroxypregnenolone, dehydroepiandrosterone (DHEA), and androstenediol, into Δ4-3-ketosteroids, including progesterone, 17α-hydroxyprogesterone, androstenedione, and testosterone, respectively.[1] Consequently, trilostane inhibits the production of all classes of steroid hormones, including androgens, estrogens, progestogens, glucocorticoids, and mineralocorticoids.[1]

The mechanism of action of trilostane in Cushing's syndrome and Conn's syndrome is by inhibiting the production of corticosteroids such as cortisol and aldosterone in the adrenal glands.[16][17] Trilostane has also been used as an abortifacient due to its inhibition of progesterone synthesis.[1][18]

Trilostane is not an aromatase inhibitor and hence does not inhibit the conversion of androgens like androstenedione and testosterone into estrogens like estrone and estradiol.[1] However, trilostane may nonetheless inhibit estrogen synthesis by inhibiting androgen synthesis.[1]

In addition to steroidogenesis inhibition, trilostane has been found to act as a noncompetitive antiestrogen, via direct and presumably allosteric interactions with the estrogen receptor.[1][19][20] The effectiveness of trilostane in postmenopausal breast cancer may relate to this apparent antiestrogenic activity.[1][19][20] Trilostane has also been found to act as an agonist of the androgen receptor.[21] As such, its use in men with prostate cancer may warrant caution.[1]

Pharmacokinetics

[edit]

Trilostane is metabolized in the liver.[1] The major metabolite of trilostane is 17-ketotrilostane.[1] The conversion of trilostane into 17-ketotrilostane is reversible, suggesting that trilostane and 17-ketotrilostane undergo interconversion in the body.[1] 17-Ketotrilostane circulates at 3-fold higher levels than trilostane and is more active than trilostane as a 3β-HSD inhibitor.[1] The elimination half-lives of trilostane and 17-ketotrilostane are both 1.2 hours, with both compounds cleared from the blood within 6 to 8 hours of a dose of trilostane.[1] 17-Ketotrilostane is excreted by the kidneys.[1]

Chemistry

[edit]

Trilostane, also known as 4α,5-epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile, is a synthetic androstane steroid and a derivative of 5α-reduced androstane derivatives like 3α-androstanediol, 3β-androstanediol, and dihydrotestosterone.[6]

Synthesis

[edit]

Trilostane is prepared from testosterone in a four-step synthesis.[citation needed]

History

[edit]

Trilostane was withdrawn from human use in the United States market in April 1994.[22][23][10] It continued to be available in the United Kingdom for use in humans under the brand name Modrenal for the treatment of Cushing's disease and breast cancer in humans, but was eventually discontinued in this country as well.[10][24][25][26]

Trilostane was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl.[27] It was available by prescription in the United Kingdom for dogs under the Vetoryl brand name for some time before it was approved in the United States.[12] The drug is also used to treat the skin disorder Alopecia X in dogs.[22][28][29]

Trilostane was the first drug approved to treat both pituitary- and adrenal-dependent Cushing's in dogs.[citation needed] Only one other drug, Anipryl (veterinary brand name) selegiline, is FDA-approved to treat Cushing's disease in dogs, but only to treat uncomplicated, pituitary-dependent Cushing's.[30] The only previous treatment for the disease was the use of mitotane (brand name Lysodren) off-label.[31][32]

A number of compounding pharmacies in the United States sell trilostane for dogs.[citation needed] Since the United States approval of Vetoryl in December 2008,[27] compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl.[33]

Society and culture

[edit]
[edit]

In March 2024, the Committee for Veterinary Medicinal Products (CVMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the veterinary medicinal product Trilocur, oral suspension for dogs.[2] The applicant for this veterinary medicinal product is Emdoka.[2] In March 2024, the CVMP adopted a positive opinion, recommending the granting of a marketing authorization for the veterinary medicinal product Trilorale, oral suspension for dogs.[3] The applicant for this veterinary medicinal product is Axience.[3] Trilocur and Trilorale were approved for medical use in the European Union in May 2024.[34][35]

Generic names

[edit]

Trilostane is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[6][7] Its developmental code name was WIN-24,540.[6][7]

Brand names

[edit]

Trilostane has been marketed under a number of brand names including Desopan, Modrastane, Modrenal, Trilox, Vetoryl, Oncovet TL and Winstan.[6][7]

Availability

[edit]

Trilostane is available for veterinary use in countries throughout the world.[36]

Veterinary uses

[edit]

Trilostane is used for the treatment of Cushing's syndrome in dogs. The safety and effectiveness of trilostane for this indication were shown in several studies.[26][31] Success was measured by improvements in both blood test results and physical symptoms (normalized appetite and activity level, and decreased panting, thirst, and urination).[26][31]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Trilostane

View on Grokipedia
from Grokipedia
Trilostane is a synthetic, competitive inhibitor of the enzyme (3β-HSD), which plays a key role in adrenal steroid biosynthesis, and it is primarily utilized in to manage hyperadrenocorticism, commonly known as , in dogs by reducing excessive production. Marketed under the brand name Vetoryl, it is administered orally in capsule form and is the only FDA-approved specifically for this condition in both pituitary-dependent and adrenal-dependent forms (as of 2023), requiring lifelong treatment with regular monitoring to avoid adrenal suppression. The mechanism of action involves blocking the conversion of to progesterone and subsequent intermediates, thereby inhibiting the synthesis of glucocorticoids like while having minimal impact on mineralocorticoids at therapeutic doses. This targeted inhibition helps alleviate clinical signs of , such as increased thirst, urination, appetite, pot-bellied appearance, and , with suppression typically within 1-2 days of starting and clinical improvements noticeable within weeks. In off-label applications, trilostane has been used for in cats and for alopecia X (a form of symmetric ) in dogs, though evidence for these uses is more limited. Originally developed in the 1970s for human use in treating and postmenopausal , trilostane was withdrawn from the market in April 1994 due to commercial reasons rather than safety concerns, but it remains available in the for similar indications (as of 2024). In veterinary practice, it has become a cornerstone treatment since its approval for dogs in 2008, offering a reversible alternative to more aggressive therapies like , though it demands careful dosing—typically 2-3 mg/kg once daily with food (FDA range 2.2-6.7 mg/kg)—and frequent ACTH stimulation tests to adjust levels and prevent overdose. Trilostane requires careful monitoring due to potential side effects and risks, including the possibility of hypoadrenocorticism; see relevant sections for details on adverse effects and contraindications. Overall, trilostane's efficacy in controlling hypercortisolism has made it a preferred option, improving for affected pets when managed appropriately.

Uses

Human medicine

Trilostane was primarily employed in for the treatment of , where it inhibited adrenal steroidogenesis to suppress excessive production. This application targeted both pituitary-dependent and adrenal-dependent forms of the condition, serving as a medical alternative to or in select cases. Clinical studies demonstrated its ability to reduce serum levels, though responses varied among patients. In addition to Cushing's syndrome, trilostane found short-term use in managing Conn's syndrome, or primary , by blocking the synthesis of aldosterone and other steroids, thereby alleviating and associated with the disorder. It was administered as a bridge therapy until definitive interventions like could be performed. Furthermore, trilostane was investigated as an adjunctive agent in postmenopausal , particularly in advanced or tamoxifen-resistant cases, where it was combined with corticosteroids such as dexamethasone or to disrupt steroid-dependent tumor growth. Typical oral dosing regimens for began at 60 mg four times daily (240 mg total per day), with adjustments made based on monitoring of levels and clinical response, sometimes escalating to 960 mg or higher in cases. Despite these applications, trilostane's human use was discontinued due to commercial reasons. It was withdrawn from the market in April 1994 but remains available in the under the brand name Modrenal.

Veterinary medicine

Trilostane is approved by the U.S. (FDA) for the treatment of both pituitary-dependent hyperadrenocorticism (PDH) and adrenal-dependent hyperadrenocorticism (ADH), collectively known as , in dogs. This approval, under the brand name Vetoryl, addresses the overproduction of by the adrenal glands, helping to manage clinical signs such as , , pot-bellied appearance, and . In , similar formulations including Trilocur and Trilorale received marketing authorization from the in May 2024 specifically for canine PDH and ADH. Trilostane has also been used off-label to treat in cats, though evidence is limited. An off-label application of trilostane in includes the treatment of Alopecia X, a growth hormone-responsive dermatosis primarily affecting breeds like Pomeranians and Siberian Huskies, where it promotes regrowth by modulating steroidogenesis. Studies have shown complete regrowth in approximately 85% of treated Pomeranians and miniature poodles within 4 to 8 weeks. The standard initial dosage for trilostane in dogs with is 1 to 3 mg/kg body weight administered once daily with food to enhance absorption and reduce gastrointestinal upset. Dosage adjustments are made based on ACTH tests, which measure levels before and 4 to 6 hours after administration to ensure therapeutic suppression without risking hypoadrenocorticism. Monitoring protocols typically include ACTH testing 10 to 14 days after starting or dose changes, followed by evaluations at 1, 3, and 6 months, with ongoing assessments every 3 to 6 months thereafter, alongside clinical sign evaluation and serum biochemistry. Clinical efficacy for trilostane in PDH is well-documented, with remission rates of clinical signs ranging from 70% to 80% in treated dogs, including resolution of in about 70% of cases and improvement in dermatologic symptoms in over 60%. While generally effective and safe, trilostane therapy requires vigilant monitoring due to potential adverse effects in animals, as detailed in the Adverse effects section.

Contraindications and precautions

In humans

Trilostane is contraindicated in and due to potential risks to the or . It is also contraindicated in children. Precautions include the need for concurrent replacement therapy when used for postmenopausal . For treatment, regular monitoring of plasma electrolytes and circulating corticosteroids is required. There is an increased risk of when trilostane is used with potassium-sparing diuretics, , amiloride, triamterene, supplements, ACE inhibitors, antagonists, nonsteroidal agents, or cyclosporine. Given its withdrawal from the market in the , use in humans is historical and not recommended without specialist oversight.

In animals

Trilostane is contraindicated in dogs with known hypersensitivity to the drug, primary hepatic disease, renal insufficiency, or pregnancy, as it has teratogenic effects and can cause early pregnancy loss. Precautions include using trilostane with caution in dogs with pre-existing kidney or liver impairment, nursing females, or breeding males, as safety has not been fully evaluated in these groups. It should be used cautiously with ACE inhibitors or potassium-sparing diuretics due to potential additive effects on aldosterone suppression, increasing the risk of electrolyte imbalances. Pregnant handlers should avoid direct contact with capsules. Prior to initiation, a thorough history and physical examination are recommended to rule out underlying conditions. If switching from mitotane, wait at least one month and monitor adrenal function closely. Vigilant monitoring with ACTH stimulation tests is essential to prevent hypoadrenocorticism.

Adverse effects

In humans

Trilostane's adverse effects in humans arise from its inhibition of key enzymes in steroid biosynthesis, leading to disruptions in adrenal and gonadal production. Common gastrointestinal effects include , , , , and . Endocrine-related adverse effects encompass symptoms of , such as , asthenia, and , due to reduced synthesis, which may require supplementation. In women, menstrual irregularities have been reported, alongside potential impacts on steroid levels. Less common adverse effects include , paresthesias, , flushing, and symptoms like or . Rare reports note granulocytopenia. Due to its withdrawal from the market, data on adverse effects in humans is primarily from pre-1994 studies and limited post-marketing reports. These tolerability issues, combined with limited efficacy in controlling , contributed to trilostane's withdrawal from the human market in the . Patients at risk for should be monitored closely, as detailed in contraindications.

In animals

Trilostane is commonly employed in veterinary practice to manage hyperadrenocorticism in dogs. In canine patients, the most frequently reported adverse effects are gastrointestinal in nature, including anorexia, , and , with incidences ranging from 10% to 25% and typically resolving without intervention as they are often mild and transient. More serious adverse effects arise from excessive adrenal suppression, potentially leading to iatrogenic hypoadrenocorticism or an Addisonian crisis, characterized by , , and electrolyte disturbances such as and ; the cumulative incidence of hypoadrenocorticism is up to 15% by 2 years and 26% by 4.3 years, mostly transient, while severe Addisonian crises occur in approximately 0% to 3% of cases and require prompt recognition through monitoring. Addisonian crises, though rare, can be life-threatening and have been associated with isolated fatalities in treated dogs. Rare adverse effects include , evidenced by elevated liver enzymes in a subset of dogs following treatment initiation, and cutaneous reactions such as pruritus, redness, or potentially indicative of . Effective of these adverse effects emphasizes vigilant monitoring via ACTH stimulation tests and clinical assessments; strategies include temporary withholding or dose reduction of trilostane, often by 50%, alongside supportive interventions like intravenous fluids, correction, and supplementation during crises to facilitate recovery and safe reinitiation of therapy.

Pharmacology

Mechanism of action

Trilostane acts as a reversible and competitive inhibitor of (), a crucial in the biosynthetic pathway that catalyzes the oxidation-isomerization of Δ⁵-3β-hydroxysteroids (such as and dehydroepiandrosterone) to their corresponding Δ⁴-3-keto forms (such as progesterone and ). This inhibition prevents the conversion of to progesterone, thereby blocking the synthesis of all downstream hormones derived from progesterone, including mineralocorticoids, glucocorticoids, androgens, and estrogens. The competitive nature of this inhibition arises from trilostane's structural of substrates, allowing it to bind to the 's , particularly involving interactions with residues like Ser124. In the adrenal glands, trilostane primarily targets the type II isoform of 3β-HSD (3β-HSD2), which is the predominant form expressed in adrenocortical cells responsible for and production. By inhibiting this isoform, trilostane reduces the synthesis of and aldosterone, key hormones in stress response and balance, respectively, while also diminishing adrenal production. At lower doses, the inhibition tends to have a more pronounced effect on synthesis compared to mineralocorticoids, allowing for targeted reduction in levels with minimal disruption to aldosterone-mediated functions. Beyond the adrenals, trilostane inhibits gonadal steroid production by acting on 3β-HSD isoforms in ovarian and testicular tissues, which contributes to its potential therapeutic role in conditions like where local steroidogenesis promotes tumor growth. In breast tissue, its preferential affinity for the type I isoform (3β-HSD1) disrupts the conversion of adrenal androgens to active estrogens, thereby suppressing estrogen-dependent proliferation without severely impacting adrenal function due to relatively lower inhibition of the type II isoform. This isoform-specific activity, with 12- to 16-fold higher affinity for 3β-HSD1 over 3β-HSD2, underscores trilostane's selective modulation of peripheral steroid pathways.

Pharmacokinetics

Trilostane is rapidly absorbed following in both humans and dogs, with peak plasma concentrations achieved within 1 to 4 hours in humans and 1 to 2 hours in dogs. In dogs, absorption is enhanced when the drug is given with , leading to higher and more consistent plasma levels compared to conditions. Although exact oral figures are not well-established, trilostane demonstrates efficient gastrointestinal absorption overall, with variability influenced by intake and individual factors such as low . Limited data are available on the distribution of trilostane, but it undergoes hepatic primarily to the 17-ketotrilostane, which is approximately 1.7 times more potent as a inhibitor and circulates at higher levels than the parent compound. This involves reversible interconversion between trilostane and 17-ketotrilostane, contributing to prolonged activity despite a relatively short elimination . The of trilostane is approximately 6 to 8 hours in humans, while in dogs it averages around 2.8 hours (with a range of 1.2 to 8.7 hours). Elimination of trilostane and its metabolites occurs primarily through biliary and renal pathways, with nearly complete recovery in humans within 24 to 48 hours. In preclinical animal studies, excretion patterns vary by species: mainly fecal in rats and approximately equal fecal and urinary in monkeys, suggesting a mixed route in dogs as well via and urine. Plasma levels in dogs return to baseline within about 12 hours post-dose, supporting once- or twice-daily dosing without significant accumulation.

Chemistry

Physicochemical properties

Trilostane is a synthetic steroid compound with the molecular formula C₂₀H₂₇NO₃ and a molecular weight of 329.43 g/mol. It features a steroid backbone derived from 5α-androst-2-ene, characterized by a 4α,5-epoxy bridge, β-hydroxy groups at the 3 and 17 positions, and a carbonitrile substituent at the 2-position, making it a 3β,17β-dihydroxy-4α,5-epoxy-5α-androst-2-ene-2-carbonitrile. This structure contributes to its classification as a competitive inhibitor in steroidogenesis pathways. Trilostane appears as a white to tan crystalline powder and has a of 264 °C with decomposition. It exhibits poor aqueous , approximately 0.059 g/L in water, reflecting its lipophilic nature with an (logP) of 3, which aligns with (BCS) Class II properties of low and high permeability. is higher in organic solvents such as DMSO (≥17 mg/mL), and it remains stable in at physiological pH 7.2, supporting its formulation for .

Synthesis

Trilostane is synthesized via a multi-step stereoselective process originating from testosterone (17β-hydroxyandrost-4-en-3-one), a readily available steroid precursor related to androstenedione through selective reduction at the 17-keto group. The route involves construction of a fused isoxazole ring, epoxidation, and ring-opening to install the characteristic 2-cyano and 3β-hydroxy functionalities while preserving the 5α configuration. This method, developed by Sterling-Winthrop, yields trilostane in high purity (>95%) suitable for pharmaceutical production and was detailed in their foundational patent. The initial step entails of testosterone with in the presence of to generate the 2-hydroxymethylene-androst-4-en-3-one-17β-ol intermediate, which facilitates subsequent cyclization. This is then reacted with hydrochloride under acidic conditions to form the Δ4-androsteno[2,3-d]isoxazol-17β-ol, closing the five-membered isoxazole ring across the 2,3-positions of the A-ring. These steps proceed with good efficiency, typically achieving 70-80% overall yield for the isoxazole formation. Epoxidation follows using m-chloroperbenzoic acid (mCPBA) in a suitable such as , selectively adding the oxygen across the 4,5-double bond from the α-face due to steric hindrance from the angular methyl groups, yielding the key (4α,5α,17β)-4,5-androst-2-eno[2,3-d]isoxazol-17-ol intermediate with high diastereoselectivity (>95:5 α:β ratio). This step is critical for establishing the epoxy bridge essential to trilostane's structure and activity. The final transformation involves base-mediated cleavage of the isoxazole ring in the epoxy precursor. Treatment with (1.05-1.30 equivalents) in at 40-45°C for approximately 2 hours generates the , followed by acidification with acetic acid and addition of to protonate and precipitate trilostane as the (4α,5α,17β)-4,5-epoxy-3β,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile. Isolation by filtration at 15-25°C affords the product in 95% yield without needing recrystallization, minimizing residues and enhancing industrial scalability. Key challenges in the synthesis include maintaining stereochemical integrity at the C5 and C17 positions during epoxidation and ring-opening, as epimerization can reduce potency; optimized conditions ensure <5% formation. The overall process, patented in the late by Sterling-Winthrop, remains the basis for commercial production, with refinements focusing on reagent efficiency and purity to meet pharmaceutical standards.

History

Development and early use

Trilostane was developed by Inc. in the late 1960s as a competitive inhibitor of (), an critical to adrenal and gonadal steroid biosynthesis. The compound's synthesis and potential therapeutic applications were detailed in US Patent 3,296,255, issued on January 3, 1967, to inventors Raymond O. Clinton and J. Manson, assigned to Inc., covering 2-cyano steroids including trilostane precursors and their use in inhibiting steroid production. Early clinical trials in the 1970s evaluated trilostane's efficacy in humans for conditions involving steroid excess, particularly and . A key study in 1978 tested doses of 240–960 mg/day in seven patients with , resulting in a prompt fall in plasma levels in all cases within hours, alongside rapid improvements in and clinical symptoms such as and . Initial investigations into followed in the late 1970s and early 1980s, where trilostane was combined with glucocorticoids to suppress production in postmenopausal women with advanced disease, showing partial responses in select patients. Trilostane received its initial regulatory approval in the in 1979 under the brand name Modrenal for the treatment of and advanced .

Approvals and withdrawals

Trilostane was initially approved for human use in the United States in 1984 for treating conditions such as and , but the U.S. (FDA) withdrew its approval in April 1994 due to concerns regarding safety and efficacy. The withdrawal followed reports of adverse events, including potential risks of and inconsistent therapeutic outcomes in clinical settings. While withdrawn in the US and other regions, trilostane remains available for human use in the under the brand name Modrenal. Shifting to veterinary applications, the FDA approved trilostane under the brand name Vetoryl in December 2008 for the treatment of pituitary-dependent and adrenal-dependent hyperadrenocorticism () in dogs, marking the first U.S. approval for this indication in animals. This approval was based on clinical trials demonstrating effective suppression and improvement in clinical signs with manageable side effects under veterinary supervision. In the , recent expansions include centralized marketing authorizations by the (EMA), with positive opinions adopted in March 2024 and authorizations granted on May 6, 2024, for Trilocur and for Trilorale, both as oral suspensions for treating hyperadrenocorticism in dogs. These approvals facilitate broader access across EU member states, emphasizing standardized dosing and monitoring protocols. As of 2025, trilostane remains approved for human use in the , while veterinary applications continue to expand, particularly in , where EMA authorizations support its role as a first-line for canine , reflecting ongoing regulatory confidence in its animal-specific benefits. The success of trilostane in , especially for dogs, stems from its improved tolerability when administered with rigorous monitoring, such as regular ACTH stimulation tests to prevent adrenal over-suppression. Unlike in humans, where variable and higher risks of severe adverse events contributed to withdrawals, canine protocols allow for dose adjustments based on individual responses, minimizing complications like gastrointestinal upset or imbalances while achieving sustained clinical remission in most cases. This targeted approach has established trilostane as a reliable option, with studies reporting resolution of symptoms in over 80% of treated dogs when monitoring is adhered to.

Society and culture

Trilostane has been discontinued for use in the United States since its withdrawal from the market in April 1994, and it is no longer approved or available for therapeutic applications there. Globally, its authorization for medicine has been revoked in many jurisdictions, with historical availability limited to prescription-only status where it was once permitted. It is not classified as a scheduled or under international regulations. For veterinary applications, trilostane holds approved status in several major markets. In the United States, the (FDA) granted approval under New Animal Drug Application (NADA) 141-291 in December 2008 for its use in treating pituitary-dependent and adrenal-dependent hyperadrenocorticism in dogs, restricting it to prescription by or on the order of a licensed . In the European Union, the (EMA) has authorized trilostane as a veterinary medicinal product, such as under the brand Trilocur (oral suspension for dogs), with similar prescription requirements enforced across member states. Internationally, trilostane is not included in the schedules of the conventions on narcotic drugs or psychotropic substances. and vary by country, but it is generally approved for veterinary use on a prescription basis; for example, the Pesticides and Veterinary Medicines Authority (APVMA) approved trilostane in 2009 for canine hyperadrenocorticism treatment. As of November 2025, no updates have altered its non-controlled status, maintaining emphasis on veterinary prescription oversight to ensure safe administration.

Brand names and availability

Trilostane is primarily marketed under veterinary brand names for the treatment of hyperadrenocorticism in dogs. In the United States, the primary brand is Vetoryl, manufactured by Dechra Veterinary Products, available as hard gelatin capsules in strengths of 5 mg, 10 mg, 20 mg, 30 mg, 60 mg, and 120 mg. In the European Union, Vetoryl is also authorized, alongside Trilocur (authorized holder: Chanelle Animal Health, manufactured by Emdoka), available as an oral suspension in 10 mg/ml and 50 mg/ml concentrations, and Trilorale (authorized holder: Axience, manufactured by Lelypharma), available as a 50 mg/ml oral suspension for dogs. For historical human use, trilostane was marketed in the under the brand name Modrenal by Wanskerne Ltd., but it has been discontinued following regulatory withdrawals for human applications. In the , Vetoryl is available by prescription only through licensed veterinarians and is not approved for over-the-counter sale, with distribution restricted to veterinary channels. In the , Trilocur and Trilorale received centralized marketing authorizations in May 2024, enabling availability across member states via veterinary prescription. Generic versions of trilostane are limited, with no FDA-approved human or veterinary generics currently available in the US; however, compounding pharmacies such as Wedgewood Pharmacy and CareFirst Specialty Pharmacy provide custom-formulated capsules, tablets, or suspensions in various strengths tailored to individual canine patients under veterinary prescription. This compounding option addresses needs for non-standard doses but is subject to FDA oversight on quality and potency.

References

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