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EFFECT OF CARDIOPULMONARY BYPASS ON ERYTHROPOIETIN PHARMACOKINETICS

¹ Department of Anesthesia, Toronto General Hospital, University Health Network, University of Toronto, 200 Elizabeth Street, M5G 2C4, Toronto, Ontario.
² Global Clinical Pharmacokinetics and Clinical Pharmacology, Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ

INTRODUCTION: Recent studies have demonstrated improved neurological outcome in patients suffering ischemic stroke treated with exogenous erythropoietin (r-huEPO). This observation raises the possibility that r-huEPO may have neuroprotectant properties that could be exploited in patients undergoing coronary artery bypass. It is hypothesized that the PK profile of r-huEPO may be altered during cardiopulmonary bypass (CPB) due to the increase in circulatory volume, blood loss, and adsorption onto the CPB circuit resulting in reduced bioavailability of r-huEPO. The objective of this study was to examine the pharmacokinetics of r-huEPO in patients undergoing CPB.

METHODS: Following REB approval patients undergoing CPB were enrolled into one of 3 groups: Control (n=6), 250 units/kg r-huEPO (n=3), and 500 units/kg r-huEPO (n=3). The r-huEPO was administered immediately prior to the induction of anesthesia. Erythropoietin blood levels were measured at baseline, 5 min after dosing, after sternotomy, on bypass (5, 15, 30, 45, 60 min) and after separation from CPB (5, 15, 45, and 60 min, 6, 12 and 24 hour and daily until day 5). Serum erythropoietin concentrations were measured using a validated enzyme-linked immunosorbent assay. Model-independent pharmacokinetic analyses were conducted using WinNonlin software, Version 3.1A (Scientific Consulting Inc., North Carolina).

RESULTS: Endogenous erythropoietin levels increased within the first 24 hours of surgery and remained elevated at levels up to 120 mIU/mL for the duration of the study period. There was a 30–40% decrease in serum concentration of r-huEPO at the initiation of CPB. Despite this decrease, there were no apparent differences in volume of distribution of the central compartment (42.2 ± 9.9, 39.8 ± 6.3 mL/kg), clearance (4.63 ± 1.14, 3.44 ± 0.68 mL/h/kg) and t_1/2 (10.7 ± 2.7, 7.99 ±2.51 h) between the treatment groups.

CONCLUSIONS: The PK of r-huEPO appeared to be unchanged during and after CPB such that we can predict the serum concentration of the drug based on the dose administered. Data from this work will be used to develop PK models to predict levels of r-huEPO in the cerebral spinal fluid and to guide in the development of a randomized control trial to test the neuroprotective properties of r-huEPO in cardiac surgery.

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