The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor

Objectives: Recombinant tissue factor pathway: inhibitor (rTFPI) has been s hown to be an effective treatment in animal models of sepsis and is under i nvestigation for human use. Reduced liver blood flow during septic shock ma y substantially alter the pharmacokinetics of rTFPI because clearance of rT FPI approaches liver blood flow. The aim of this study was to examine the e ffect of exercise-induced reduction in liver blood flow on the pharmacokine tics and pharmacodynamics of rTFPI. Methods: This was a two-way, open-label, randomized crossover study in eigh t healthy male volunteers. The subjects in both treatment groups received a continuous intravenous infusion of rTFPI (0.2 mg/kg/h) concurrently with i ntravenous sorbitol(50 mg/min) for 4 hours. Sorbitol mns used as a biomarke r for liver blood flow, The subjects were randomized to remain supine or to exercise on a bicycle ergometer for 30 minutes starting at the beginning o f the third hour of the infusion. Results: Exercise reduced liver blood now (mean +/- SEM) from 1.44 +/- 0.06 L/min to 0.40 +/- 0.03 L/min, The average clearance of rTFPI decreased fro m 0.73 +/- 0.04 L/min in the supine position to 0.25 +/- 0.02 L/min during exercise, This decrease in rTFPI clearance resulted in an 80% (95% confiden ce interval [CI], 60% to 102%) increase in plasma rTFPI levels during exerc ise, The average maximal prothrombin time and activated partial thromboplas tin time values during exercise mere 1.4 (95% CI, 0.4 to 2.5) and 4.4 (95% CI, 2.7 to 6.1) seconds higher compared with the supine steady-state level, Conclusions: Reduction in liver blood flow by exercise markedly increased r TFPI concentrations and induced a slight but variable prothrombin time and activated partial thromboplastin time increase at the rTFPI dose studied.