Palladia (Toceranib)

Tyrosine Kinase Inhibitor Antineoplastic Agent

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 3.25 mg/kg (range 2.75-3.5 mg/kg) Every other day (e.g., Monday, Wednesday, Friday) Duration: Continuous until disease progression or unacceptable toxicity; typically evaluated at 4-6 weeks for response
Notes: Administer with food to reduce GI upset and enhance absorption. Dose adjustments may be needed based on toxicity (e.g., reduce to 2.75 mg/kg or increase interval to every 72 hours).
Cat PO 2.5-3.0 mg/kg Every other day Duration: Variable; based on response and tolerance
Notes: Limited data; use with caution and monitor for adverse effects.

Clinical Indications & Species Uses

General Indications
  • Treatment of canine mast cell tumors (approved)
  • Off-label use for other canine tumors
Dog (Canine)
  • Treatment of Patnaik grade II or III recurrent, cutaneous mast cell tumors with or without regional lymph node involvement
  • Treatment of non-resectable mast cell tumors
  • Treatment of various solid tumors (off-label): anal sac adenocarcinoma, thyroid carcinoma, head and neck squamous cell carcinoma, metastatic osteosarcoma, and others

Pharmacology & Mechanism of Action

Drug Class: Tyrosine Kinase Inhibitor | Pharmacological Group: Antineoplastic Agent

Mechanism of Action: Toceranib is a small molecule receptor tyrosine kinase inhibitor that selectively inhibits several receptor tyrosine kinases involved in tumor growth and angiogenesis. It primarily targets vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (KIT). By inhibiting these kinases, toceranib blocks downstream signaling pathways (e.g., PI3K/AKT, MAPK) that promote tumor cell proliferation, survival, and metastasis. Additionally, it inhibits KIT mutations that are constitutively active in certain canine mast cell tumors, leading to apoptosis and reduced tumor growth.

Pharmacodynamics: Toceranib exhibits antitumor activity by inhibiting angiogenesis (via VEGFR), tumor cell proliferation (via PDGFR and KIT), and by modulating the tumor microenvironment. It also has immunomodulatory effects, including inhibition of regulatory T cells and enhancement of natural killer cell activity. In clinical studies, toceranib has shown objective response rates in canine mast cell tumors, particularly those with KIT mutations, and has been used for other solid tumors. The pharmacodynamic effects are dose-dependent, with higher doses associated with increased toxicity but also potentially greater efficacy.

⚡ Pharmacokinetics Summary

Absorption: Toceranib is well absorbed after oral administration in dogs, with peak plasma concentrations achieved within 2-4 hours. Food can increase absorption, so it is recommended to administer with food to enhance bioavailability and reduce gastrointestinal upset.
Distribution: Toceranib is extensively distributed into tissues, with a large volume of distribution. It is highly protein-bound (approximately 90%) in plasma. It crosses the blood-brain barrier to a limited extent.
Metabolism: Toceranib is primarily metabolized in the liver via cytochrome P450 enzymes (CYP3A4 and CYP1A2) to several metabolites, some of which are pharmacologically active. The main metabolic pathways include oxidation and demethylation.
Excretion: Toceranib and its metabolites are excreted primarily in feces (approximately 70%) and to a lesser extent in urine (approximately 20%). Biliary excretion is a major route of elimination.
Half-Life: The terminal half-life in dogs is approximately 18-24 hours, allowing for every-other-day dosing.
Bioavailability: Oral bioavailability is approximately 70-80% in dogs when administered with food; it may be lower when given on an empty stomach.
Protein Binding: Approximately 90% protein-bound in canine plasma.

Available Formulations & Strengths

Oral Tablet 10 mg, 15 mg, 50 mg (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to toceranib or any component of the formulation
  • Use in animals with severe hepatic or renal impairment (caution)
  • Use in pregnant or lactating animals (teratogenic potential)
  • Concurrent use with strong CYP3A inhibitors or inducers (may alter metabolism)
Warnings & Clinical Precautions:
  • Toceranib is a potent drug; handle with care (avoid skin contact, wear gloves)
  • May cause gastrointestinal toxicity (diarrhea, vomiting, anorexia); manage symptomatically
  • Monitor complete blood count and serum chemistry regularly (neutropenia, thrombocytopenia, elevated liver enzymes)
  • May cause proteinuria; monitor urine protein:creatinine ratio
  • Use with caution in animals with pre-existing cardiac disease (potential for QT prolongation)
  • Not for use in animals intended for breeding; may impair fertility
  • Do not crush or split tablets; avoid inhalation of powder
  • Keep out of reach of children and pets

Adverse Effects & Reactions

Common:

  • Diarrhea
  • Vomiting
  • Anorexia
  • Weight loss
  • Lethargy
  • Neutropenia
  • Elevated liver enzymes (ALT, AST)

Serious / Severe:

  • Protein-losing nephropathy (proteinuria)
  • Gastrointestinal ulceration or perforation
  • Severe neutropenia or thrombocytopenia
  • Hepatotoxicity
  • Pancreatitis
  • Pulmonary fibrosis (rare)

Rare:

  • Cardiac arrhythmias (QT prolongation)
  • Seizures
  • Stevens-Johnson syndrome
  • Bone marrow aplasia

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) May increase toceranib plasma concentrations, increasing toxicity risk High
CYP3A inducers (e.g., phenobarbital, rifampin) May decrease toceranib plasma concentrations, reducing efficacy Moderate
NSAIDs (e.g., carprofen, meloxicam) Increased risk of gastrointestinal ulceration and bleeding High
Corticosteroids (e.g., prednisone) May increase risk of gastrointestinal ulceration and immunosuppression Moderate
Other chemotherapeutic agents (e.g., doxorubicin) Additive myelosuppression and gastrointestinal toxicity High

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe vomiting and diarrhea
  • Dehydration
  • Neutropenia and thrombocytopenia
  • Gastrointestinal ulceration or hemorrhage
  • Hepatotoxicity
  • Renal toxicity (proteinuria, azotemia)

Emergency Treatment Protocol: There is no specific antidote. Treatment is symptomatic and supportive: induce emesis if recent ingestion (within 2 hours) and activated charcoal may be considered. Provide intravenous fluids for dehydration, antiemetics (e.g., maropitant), gastroprotectants (e.g., omeprazole, sucralfate), and antibiotics if neutropenic. Monitor blood counts, serum chemistry, and urine protein. In severe cases, hospitalization and intensive care may be required.

Food Animal Withdrawal Times

Not approved for use in food animals. Withdrawal times are not established. Do not use in animals intended for human consumption.

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)

Light Sensitivity: Light-sensitive — protect from direct exposure.

Handling & Special Conditions: Protect from light and moisture. Keep in original container. Do not remove desiccant. Keep out of reach of children and pets.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Approved by FDA for use in dogs (Palladia, Zoetis) for the treatment of Patnaik grade II or III recurrent, cutaneous mast cell tumors with or without regional lymph node involvement.

Extra-Label (Off-Label) Use: In the US, toceranib is FDA-approved for dogs. Extra-label use in other species or for other indications is permitted under AMDUCA (Animal Medicinal Drug Use Clarification Act) only by or on the order of a licensed veterinarian within a valid veterinarian-client-patient relationship. For food animals, extra-label use is prohibited if it results in residues in edible tissues.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Toceranib (Palladia) is a valuable targeted therapy for canine mast cell tumors, especially those with KIT mutations. It is generally well-tolerated, but close monitoring for gastrointestinal and hematologic toxicity is essential. Dose adjustments are common based on adverse effects. It is important to administer with food to improve absorption and reduce GI upset. Baseline and periodic monitoring should include CBC, serum chemistry, urinalysis with protein:creatinine ratio, and blood pressure. Toceranib may also be used off-label for other tumors, but evidence is less robust. Client education on handling precautions and potential side effects is crucial. In cats, use is limited and should be done with caution due to increased sensitivity to adverse effects. Always consider potential drug interactions, especially with NSAIDs and corticosteroids. For refractory cases, combination with other therapies (e.g., surgery, radiation) may be considered.

References & Literature

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