Preclinical evaluation of alpha-1-proteinase inhibitor. Pharmacokinetics and safety studies

To assess the pharmacodynamics and safety of alpha-1-proteinase inhibitor (human) (A1PI) isolated from pooled human plasma, a series of animal studies was conducted. Using both unlabeled and 125I-labeled A1PI (highly purified), plasma residence time and tissue distribution were determined in rabbits. A catabolic half-life of 48.5 hours was obtained for the labeled material, which agreed well with the antigenic decay (35.5 hours), measured with a specific enzyme-linked immunosorbent assay, and the functional activity decay (38.1 hours), measured antigenically by the ability of resident human A1PI to complex with human neutrophil elastase. No unusual tissue distribution was observed at the first, 24th, or 168th hour of sacrifice. Cynomolgous monkeys received infusions of labeled A1PI and a catabolic half-life of 55.45 hours was obtained; infusion of unlabeled material yielded anticipated plasma recovery and a significant increment in A1PI in bronchial-alveolar lavage fluid, both antigenically and functionally determined. Safety studies assessing acute physiologic response and both acute and subacute toxicity presented no significant adverse effects. We conclude that A1PI (human) presents normal pharmacodynamics and safety and is therefore associated with a wide margin of safety for the intended clinical applications.