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The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor
Author(s) -
Kemme Michiel J. B.,
Burggraaf Jacobus,
Schoemaker Rik C.,
Paulson Susan,
Karim Aziz,
Lentjes Eef G. W. M.,
Childs Anne,
Braeckman Rene A.,
Cohen Adam F.
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.106796
Subject(s) - medicine , pharmacokinetics , crossover study , partial thromboplastin time , pharmacodynamics , hematocrit , prothrombin time , anesthesia , pharmacology , coagulation , placebo , pathology , alternative medicine
Objectives Recombinant tissue factor pathway inhibitor (rTFPI) has been shown to be an effective treatment in animal models of sepsis and is under investigation for human use. Reduced liver blood flow during septic shock may substantially alter the pharmacokinetics of rTFPI because clearance of rTFPI approaches liver blood flow. The aim of this study was to examine the effect of exercise‐induced reduction in liver blood flow on the pharmacokinetics and pharmacodynamics of rTFPI. Methods This was a two‐way, open‐label, randomized crossover study in eight healthy male volunteers. The subjects in both treatment groups received a continuous intravenous infusion of rTFPI (0.2 mg/kg/h) concurrently with intravenous sorbitol (50 mg/min) for 4 hours. Sorbitol was used as a biomarker 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 of the third hour of the infusion. Results Exercise reduced liver blood flow (mean ± SEM) from 1.44 ± 0.06 L/min to 0.40 ± 0.03 L/min. The average clearance of rTFPI decreased from 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% confidence interval [CI], 60% to 102%) increase in plasma rTFPI levels during exercise. The average maximal prothrombin time and activated partial thromboplastin time values during exercise were 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 rTFPI concentrations and induced a slight but variable prothrombin time and activated partial thromboplastin time increase at the rTFPI dose studied. Clinical Pharmacology & Therapeutics (2000) 67 , 504–511; doi: 10.1067/mcp.2000.106796