PURPOSE: Eight in vivo preclinical protocols were conducted to assess the profile of A1PI Fraction (Fr.) IV-1 paste in comparison to A1PI using Fr. IV-1+4 paste regarding biocomparability.
METHODS: The following biocomparability studies were conducted with A1PI Fr.IV-1 and Fr.IV-1+4: safety pharmacology in dogs (measurement of mean arterial and pulmonary artery pressure, cardiac output, stroke volume, total peripheral vascular resistance, heart rate, respiration rate, respiratory minute volume, ECG, platelet count and plasma fibrinogen concentration), bronchospastic activity in guinea pigs, hypotensive potential in spontaneously hypertensive rats (all determining anaphylactoid potential), pharmacokinetics (PK) in rats, acute and 30 day repeated dose toxicity including toxicokinetics in rats and a local tolerance study in rabbits. Negative reference items were administered using corresponding volumes.
RESULTS: Safety pharmacology testing in dogs, rats and guinea pigs showed neither anaphylactoid reactions nor development of disseminated intravascular coagulation after treatment with either A1PI Fr.IV-1, A1PI Fr.IV-1+4 or negative reference items. Positive reactions were induced in all animals by the subsequent injection of the immunoglobulin positive control, confirming the validity of the models. Pharmacokinetics: there were no significant differences in area under the curve and half life for test and reference items. Toxicology profile: there were no significant changes in any of the parameters evaluated. No antibody responses were detected. No substantial sex differences were observed in toxicokinetics during repetitive dose administration, steady state levels of A1PI were reached by day fifteen. Neither abnormalities in animal behavior nor alterations at the injection sites were observed in any group during local tolerance testing.
CONCLUSION: In all preclinical animal studies A1PI from Fr.IV-1 was bioequivalent to Fr.IV-1+4 regarding safety and PK.
CLINICAL IMPLICATIONS: Based on preclinical results, no differences regarding safety and efficacy can be expected in the clinical use of A1PI products from either Fr.IV-1 or Fr.IV-1+4 paste.
DISCLOSURE: Eva Muchitsch, Employee All authors are employees of Baxter BioScience.