PHYSIOLOGY AND PHARMACOKINETICS OF A NOVEL HEMOGLOBIN-BASED OXYGEN CARRIER IN HUMANS

Objective: To evaluate the physiology and pharmacokinetics of a novel hemoglobin based oxygen carrier of bovine origin. Design: Randomized, single-blind, placebo-controlled, dose-escalation study, Setting: The Upjohn Research Clinics (Kalamazoo, MI), Subjects: Normal healthy adul t men between the ages of 18 and 45 yrs, There were 18 subjects who re ceived active treatment and 23 controls, Interventions: All subjects h ad phlebotomy of 15% of blood volume (performed in <15 mins) followed by isovolemic hemodilution (3:1, Ringer's lactate to the volume of who le blood removed) over a 90-min period, and either active drug (polyme rized bovine hemoglobin) or a control infusion of lactated Ringer's so lution (each infusion given over a total of 4.3 hrs), The subjects ran domized to active treatment received a loading dose and a continuous i nfusion of polymerized bovine hemoglobin for a total dose of 16.5, 24. 1, 30.2, 38.0, or 45.0 g. All subjects had an indwelling radial artery catheter (for blood pressure and arterial blood gas measurements), de termination of cardiac function (by impedance plethysmography), serial pulmonary function tests (spirometry and diffusion capacity), and met abolic cart measurements. Measurements and Main Results: Pharmacokinet ics of the plasma bovine hemoglobin demonstrated that the elimination of the hemoglobin based oxygen carrier was a linear, first-order proce ss and that there was no renal excretion, Peak plasma concentrations w ere between 1 to 2 g/dL and plasma half-life approached 20 hrs at the highest doses given, Diffusion capacity of oxygen was increased up to 20% above baseline in the 38.0 and 45.0 g groups in comparison with co ntrols (similar to 14% below baseline) between 2 and 24 hrs after the infusion (p < .01), Other pulmonary function tests and arterial blood gas measurements were unremarkable. Arterial oxygen content and oxygen delivery tended to be greater in active groups than in controls, Conc lusions: The plasma concentrations of bovine hemoglobin were directly proportional to the doses administered, An in crease in diffusion capa city paralleled the plasma bovine hemo globin concentrations, Dosing o f the hemoglobin-based oxygen carrier of bovine origin to a target pla sma hemoglobin concentration can be achieved using pharmacokinetic pri nciples with measurable effects on oxygen physiology.