Abstracts

Rationale: Experimental studies of Erythropoetin (EPO) and interleukin 1 receptor antagonist (Anakinra) in models of traumatic brain injury and stroke have demonstrated a neuroprotective effect. Based on serum concentrations obtained in clinical studies in patients and extrapolation from experimental studies in rodents, average concentrations of 5,000 10,000 mIU/ml and 5.0- 10 ?g/ml were chosen for EPO and Anakinra, respectively. Published studies have demonstrated adequate brain or CSF concentration with serum concentrations in the targeted range.Methods: Single and multiple dose pharmacokinetics studies of EPO (Procrit) and Anakinra (Kineret) given by intraperitoneal (i.p.) and/or subcutaneous (s.c.) injections every 12 hrs to male Sprague Dawley rats were done to determine the appropriate dosage regiments needed to target clinically relevant concentrations . Blood was collected from a jugular catheter at 0, 1, 2, 4, 6, 12 hrs and 24 hr (single dose) and then immediately before (trough) and 1 hr (peak) after injections for 72 hrs for multiple dose studies. Serum concentrations were determined using commercially available ELISA kits. Results: EPO 5,000 IU/kg given s.c. every 12 hrs resulted in average serum concentrations increasing from 479, 827, 1,737, 2,658, 4,874 to 11,155 mIU/ml, at 1, 2, 4, 6, 12 and 24 hrs, respectively. After 24 hrs, concentrations had minimal fluctuations with peak and trough concentrations of 13,375 1411 mIU/mL and 13,395 1436 mIU/ml. EPO 2,500 IU/kg i.p. and 5,000 IU/kg i.p. doses reached concentrations of 4,481 315 mIU/ml and 10,712 5787 mIU/ml by 1 hr, with peak concentration of 12,158 2679 mIU/ml and 18,147 5831 mIU/ml at 4 hr, respectively. Serum concentrations remained elevated at 6 hrs and then decreased with an apparent elimination half-life (T1/2) of 8.7 3.4 hrs. Anakinra 100 mg/kg administered i.p. produced peak concentrations 51.9 and 47.3 ?g/ml, 1 and 2 hrs post-injection, respectively with T1/2 of 1.7 0.34 hr. After s,c. administration, there was extended absorption with average concentrations of 20.4 ?g/ml , 21.2 ?g/ml and 16.5 ?g/ml at 1, 2 and 4 hrs post-injection and a T1/2 of 5.8 2.4 hrs after 6 hrs post-injection suggesting prolonged absorption throughout the dosage interval. Conclusions: Erythropoietin 2,500 IU/Kg or Anakinra 100 m/kg administered every 12 hrs results in clinically relevant serum concentrations. The i.p.dose is rapidly absorbed and produces therapeutic serum concentration within 1-2 hrs. Subsequent doses by s.c. injections resulted in prolonged absorption allowing every 12 hr dosing to maintain the average targeted concentrations.