Polysorbate 80-Induced Anaphylactoid Reaction and the Effects on Cardiovascular Function: Dose Threshold and Species...

Area of Science:

• Pharmacology
• Toxicology
• Pre-clinical drug development

Background:

• Polysorbate 80 (PS80) is a common excipient in pharmaceutical formulations.
• Understanding PS80's safety profile, particularly cardiovascular (CV) and hypersensitivity effects, is crucial for pre-clinical studies.

Purpose of the Study:

• To determine the dose threshold for cardiovascular changes and hypersensitivity reactions to PS80 in dogs.
• To compare the effects of PS80 in dogs with those in other species like monkeys and minipigs.

Main Methods:

• PS80 was administered to dogs via intravenous bolus, intravenous infusion, subcutaneous injection, and oral gavage.
• Cardiovascular parameters (blood pressure, heart rate) and body temperature were monitored in dogs.
• Monkeys and minipigs received PS80 via intravenous infusion.
• Plasma histamine levels were measured in dogs, with and without diphenhydramine pre-treatment.

Main Results:

• In dogs, PS80 caused decreased blood pressure and increased heart rate at IV doses ≥0.5 mg/kg (bolus) and ≥1.0 mg/kg (infusion).
• Transient edema and erythema were observed across all administration routes in dogs, monkeys, and minipigs.
• Monkeys and minipigs did not exhibit CV changes or histamine release at the tested dose (3 mg/kg IV infusion).

Conclusions:

• Mild, transient skin reactions to PS80 occur in dogs at doses not associated with cardiovascular effects.
• The cardiovascular effect threshold for PS80 in dogs varies by administration route, with IV routes showing lower thresholds.
• Dogs demonstrate a species-specific sensitivity to PS80-induced cardiovascular effects compared to monkeys and minipigs.