Background: Hypoxic-ischemic (HI) brain injury is a leading cause of long-term neurodevelopmental
morbidities in neonates. Human plasma-derived Inter-Alpha Inhibitor Proteins (hIAIPs) are neuroprotective after
HI brain injury in neonatal rats. The light chain (bikunin) of hIAIPs inhibits proteases involved in the coagulation
of blood. Newborns exposed to HI can be at risk for significant bleeding in the brain and other organs.
Objective: The objectives of the present study were to assess the pharmacokinetics (PK) and the duration of bleeding
after intraperitoneal (IP) administration of hIAIPs in HI-exposed male and female neonatal rats.
Methods: HI was induced with the Rice-Vannucci method in postnatal (P) day-7 rats. After the right common
carotid artery ligation, rats were exposed to 90 min of 8% oxygen. hIAIPs (30 mg/kg, IP) were given immediately
after Sham or HI exposure in the PK study and serum was collected 1, 6, 12, 24, or 36 h after the injections.
Serum hIAIP concentrations were measured with a competitive ELISA. ADAPT5 software was used to fit the
pooled PK data considering first-order absorption and disposition. hIAIPs (60 mg/kg, IP) were given in the bleeding
time studies at 0, 24 and 48 h after HI with tail bleeding times measured 72 h after HI.
Results: IP administration yielded significant systemic exposure to hIAIPs with PK being affected markedly
including primarily faster absorption and reduced elimination as a result of HI and modestly of sex-related differences.
hIAIP administration did not affect bleeding times after HI.
Conclusion: These results will help to inform hIAIP dosing regimen schedules in studies of neuroprotection in
neonates exposed to HI.