Threshold for Anaphylactoid Reaction to Polysorbate 80 in Canines.

Area of Science:

• Pharmacology
• Toxicology
• Biopharmaceutical Formulation

Background:

• Polysorbate 80 (PS80) is a common pharmaceutical excipient used as a dispersing agent, solubilizer, and stabilizer.
• Administration of PS80, particularly at high doses, has been linked to anaphylactoid-type reactions, characterized by mast cell degranulation and histamine release.
• Canine models are sensitive to PS80, but conflicting data exists regarding the dose and route required to induce reactions.

Purpose of the Study:

• To investigate the dose-response relationship and route-dependency of Polysorbate 80-induced anaphylactoid reactions in dogs.
• To establish a threshold dose for eliciting anaphylactoid reactions in a sensitive animal model.
• To better understand the safety profile of PS80 in biopharmaceutical applications.

Main Methods:

• Conducted studies in anesthetized and conscious dogs using multiple dosing regimens of PS80.
• Administered PS80 via intravenous (IV) bolus and subcutaneous (SC) injection at various doses and concentrations.
• Monitored cardiovascular parameters, observed clinical signs, and measured biomarkers of mast cell degranulation.

Main Results:

• An intravenous bolus of 1 mg/kg PS80 (0.25% w/v) elicited a positive anaphylactoid reaction, including increased heart rate, hypotension, and clinical signs like a reddened muzzle.
• Subcutaneous injection of PS80 (0.25% w/v) up to 20 mg/kg did not result in a full anaphylactoid reaction.
• Lower IV doses (≤ 0.5 mg/kg) via bolus or infusion did not elicit a significant reaction.

Conclusions:

• The threshold dose for eliciting an anaphylactoid reaction to PS80 in canines is dependent on the route of administration and infusion rate.
• Intravenous administration requires a significantly lower dose of PS80 to induce an anaphylactoid reaction compared to subcutaneous administration.
• These findings provide critical data for the safety assessment of PS80 in pharmaceutical and biopharmaceutical products.