Verdinexor

Overview

Verdinexor (Laverdia®-CA1) is an oral antineoplastic agent conditionally approved for the treatment of lymphoma in dogs. It belongs to a novel class of anticancer drugs known as selective inhibitors of nuclear export (SINEs) and is designed to target cellular pathways involved in tumor growth and survival.

Clinical studies have demonstrated activity against both B-cell and T-cell lymphoma, with some dogs achieving partial or complete responses and others experiencing stabilization of disease. Verdinexor is administered orally and should be given immediately after a small meal, as food significantly enhances drug absorption.

In addition to lymphoma, verdinexor has shown experimental biologic activity against canine cell lines for mammary carcinoma, mast cell tumor, melanoma, osteosarcoma, and transitional cell carcinoma. The drug has also demonstrated antiviral activity, including against eastern and western equine encephalitis. However, its approved clinical use is currently limited to canine lymphoma, and the product should only be used according to label directions.

Mechanism of Action (MOA): Verdinexor is a selective inhibitor of nuclear export that reversibly blocks exportin-1 (XPO1/CRM1), a protein responsible for transporting tumor suppressor proteins and growth-regulatory proteins from the nucleus to the cytoplasm. By preventing this export, verdinexor promotes retention of these regulatory proteins within the nucleus, enhancing apoptosis and inhibiting the survival of malignant cells.

Indications

Verdinexor is indicated for the treatment of lymphoma in dogs and should be used only according to the approved product labeling.

• Canine lymphoma: Conditionally approved for the treatment of dogs with B-cell or T-cell lymphoma. Field-study response rate 34.5% (CR + PR in 20 of 58 dogs). Median time to tumor progression 29.5 days overall, with 43 days in naïve lymphoma patients vs 24 days in relapsed patients.
• Cats: NOT indicated in cats.

Dosage (Reference)

Dog

Verdinexor is administered orally for the treatment of lymphoma and should be given immediately after feeding. Doses are administered twice weekly with a minimum interval of 72 hours between treatments.

Warnings & Precautions

Verdinexor is an antineoplastic agent with significant gastrointestinal, hematologic, and reproductive safety considerations. Careful patient selection and monitoring are recommended throughout treatment.

• Use only as labeled: Verdinexor is conditionally approved for canine lymphoma and should only be used according to approved labeling directions.
• Pregnancy and breeding: Contraindicated in dogs that are pregnant, lactating, or intended for breeding due to the risk of reproductive and developmental toxicity.
• Hypersensitivity: Do not administer to dogs with a known hypersensitivity to verdinexor or any component of the formulation.
• Body weight limitations: Dogs weighing less than 9 kg may not be accurately dosed or undergo appropriate dose adjustments.
• Administration with food: The drug should be given immediately after feeding, as food substantially increases oral absorption.
• Appetite suppression: Anorexia is the most common dose-limiting adverse effect, reported in 45-74% of dogs in the field study. Appetite stimulants appropriate for dogs and low-dose corticosteroids may be needed to maintain food intake during therapy.
• Unstudied patient populations: Safety has not been established in dogs younger than 7 months of age or in dogs with diabetes mellitus, significant cardiovascular, hepatic, or renal disease.
• Concurrent illness: Use has not been adequately evaluated in dogs with serious infections, concurrent malignancies, or clinically significant hypercalcemia.
• Handling precautions: Wear chemotherapy-resistant disposable gloves when handling verdinexor, broken tablets, or the dog’s bodily fluids/waste for 3 days after each treatment. Clean spills with disposable absorptive materials (e.g., paper towels) and discard in a sealed plastic bag. Wash food/water bowls and toys separately from normal household laundry.
• Human exposure: Women who are pregnant, attempting to become pregnant, or breastfeeding should not handle the drug.
• Narrow margin of safety: Verdinexor has a narrow therapeutic index.
• Monitoring schedule: Phase II study performed CBC + serum chemistry (including liver enzymes, albumin, total protein) rechecks weekly during the first 28 days, then every other week. Baseline + periodic urinalysis, urine culture, and urine protein:creatinine (UPC) ratio recommended.
• Fertility: Verdinexor can affect male and female fertility

Drug Interactions

Limited information is available regarding the effects of concurrent medications on verdinexor metabolism. Most interaction concerns involve reduced vaccine efficacy, potential toxicity with certain drugs, or combinations that have not been adequately studied.

• Vaccines: Verdinexor may reduce the immune response to vaccination, potentially decreasing vaccine effectiveness.
• Other chemotherapeutic agents: The safety and effectiveness of concurrent use with other chemotherapy drugs have not been established.
• The product label cautions that concurrent administration of verdinexor with drugs that undergo glutathione conjugation (eg, acetaminophen) should be minimized.
• Possible substrates of glutathione S-transferase include: Acetaminophen (metabolite), Anthracyclines (eg, doxorubicin, mitoxantrone), Busulfan, Cisplatin, Cyclophosphamide, Spinosad and Thiotepa)
• Documented co-administered drugs (no significant interactions): Concomitantly studied in the field trial (no clinically significant interactions noted): corticosteroids (e.g., prednisone/prednisolone), proton pump inhibitors (e.g., omeprazole), H2 antagonists (e.g., famotidine), antibiotics, antiemetics (e.g., ondansetron), GI motility modifiers (e.g., loperamide, metoclopramide), and opioids (e.g., morphine).

Side Effects & Overdose

Side Effects

Adverse effects of verdinexor are common and generally dose-related. Gastrointestinal and hematologic abnormalities are reported most frequently, and many patients experience multiple adverse effects during treatment.

• Anorexia: the most commonly reported adverse effect and a frequent dose-limiting toxicity.
• Vomiting and diarrhea: Vomiting (26-59%) and diarrhea (12-52%) are common GI effects that may require supportive care or dose adjustment.
• Weight loss: Reported in 31-48% of dogs — may occur secondary to reduced appetite and GI adverse effects.
• Lethargy and weakness: Lethargy (17-41%) and weakness are frequently reported during treatment and may affect overall activity levels.
• Polydipsia and polyuria: Polydipsia (33%) and polyuria (31%) have been observed; note concurrent corticosteroid use was common in the field study and may contribute to these effects.
• Fever, generalized pain, and cough/dyspnea: Reported in a proportion of treated patients.
• Thrombocytopenia: Reported in 31% of dogs — a common hematologic toxicity. As a class, SINE drugs block thrombopoietin signaling, and reversible thrombocytopenia is expected. In the field study, 2 dogs experienced bruising and 1 had epistaxis.
• Other hematologic abnormalities: Lymphopenia (29%), neutrophilia (26%), anemia (22%), leukopenia (21%), and neutropenia (16%) have been reported.
• Elevated liver enzymes: Elevated ALP (48%), ALT (36%), and AST (10%) may occur during therapy.
• Laboratory abnormalities: Increased BUN (26%), hypercalcemia (17%), hypochloremia (14%), hyperphosphatemia (12%), hypoproteinemia (10%), and prolonged partial thromboplastin time have been reported. A protein-losing nephropathy was reported in 1 dog.
• Urinary abnormalities: Hematuria, urinary tract infection, low urine specific gravity, and proteinuria have been observed.

Overdose

Overdose (1- 1.75 mg / kg 3 times weekly ) may result in an increased frequency and severity of the drug’s expected adverse effects, particularly gastrointestinal, hematologic, and systemic abnormalities.

• Severe gastrointestinal toxicity: Marked anorexia, vomiting, diarrhea, and progressive weight loss may occur.
• Poor body condition: Thin body condition, excessive shedding, and reduced skin elasticity have been reported following excessive exposure.
• Ocular and neurologic signs: Lacrimation, mild depression, and decreased forelimb strength may be observed.
• Hematologic abnormalities: Reductions in lymphocytes, eosinophils, and monocytes may occur.
• Laboratory changes: Increased fibrinogen, albumin, and BUN have been reported in overdose studies.
• Management: Treatment is primarily supportive: close monitoring of hydration status, hematologic parameters, and clinical condition. For suspected or confirmed overdose, consult a 24-hour veterinary poison consultation center.

Key Notes

Practical clinical points that help optimize the safe and effective use of verdinexor in dogs with lymphoma:

• Targeted anticancer therapy: Verdinexor belongs to the selective inhibitor of nuclear export (SINE) class, a mechanism that differs from traditional cytotoxic chemotherapy agents.
• Response variability: Treatment responses vary considerably among patients, ranging from disease stabilization to partial or complete tumor responses.
• Greater benefit in treatment-naïve patients: Clinical studies reported longer time to tumor progression in newly diagnosed dogs (43 days) compared with dogs treated after relapse (24 days).
• Twice-weekly administration: The dosing schedule allows treatment without daily medication, which may improve owner compliance in long-term management.
• Dose titration is often necessary: Therapy is commonly adjusted based on individual tolerance and clinical response rather than maintaining the same dose throughout treatment.
• Monitoring treatment success: Regular assessment of lymph node size, clinical signs, body weight, and overall quality of life. The phase II study performed CBC + serum chemistry rechecks weekly during the first 28 days, then every other week.
• Client communication is essential: Owners should be advised that the drug is conditionally approved and treatment goals are often disease control and quality-of-life improvement rather than cure.
• SINE class activity beyond lymphoma: Experimental biologic activity demonstrated against canine mammary carcinoma, mast cell tumor, melanoma, osteosarcoma, and transitional cell carcinoma cell lines. Antiviral activity also documented, including against eastern and western equine encephalitis.
• Storage + dispensing: Storage: tablets at room temperature 20-25°C (68-77°F); keep out of reach of children and pets; do NOT store near other drugs, food, or in food-prep areas. Include the Client Information Sheet (CIS) when dispensing; unused tablets MUST be returned to the veterinarian for disposal.
• Owner safety: Wear chemotherapy-resistant gloves when handling verdinexor and the dog’s bodily fluids/waste for 3 days after each treatment. Children and women who are pregnant, nursing, or attempting to conceive must NOT handle the drug or the dog’s waste.