A 24-Hour Continuous Infusion Study of Bivalirudin in the Rat

The potential toxic effects of bivalirudin (an anticoagulant) were evaluated in this intravenous infusion study in Sprague-Dawley rats. Bivalirudin was administered over a 24-hour period by continuous intravenous infusion to six groups of rats. Dose levels of 100, 500, and 2000 mg/kg/24 h were selec...

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Bibliographic Details
Published in:	International journal of toxicology Vol. 22; no. 3; pp. 195 - 206
Main Authors:	Gleason, Teresa G., Chengelis, Christopher P., Jackson, Carney B., Lindstrom, Pia
Format:	Journal Article
Language:	English
Published:	Los Angeles, CA SAGE Publications 01-05-2003 Taylor & Francis
Subjects:	Animals Anticoagulants - administration & dosage Anticoagulants - pharmacokinetics Anticoagulants - toxicity Biological and medical sciences Blood Specimen Collection - adverse effects Blood. Blood coagulation. Reticuloendothelial system Dose-Response Relationship, Drug Female Hemorrhage - chemically induced Hirudins - administration & dosage Hirudins - analogs & derivatives Hirudins - pharmacokinetics Hirudins - toxicity Infusions, Intravenous Longevity - drug effects Male Medical sciences No-Observed-Adverse-Effect Level Peptide Fragments - administration & dosage Peptide Fragments - pharmacokinetics Peptide Fragments - toxicity Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Recombinant Proteins - administration & dosage Recombinant Proteins - pharmacokinetics Recombinant Proteins - toxicity Rats Anticoagulant Bivalirudin Intravenous Infusion Hemorrhage Toxicokinetic Assessment Vertebrata Mammalia Intravenous administration Peptides Rat Perfusion Polypeptide Animal Rodentia Pharmacokinetics
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Summary:	The potential toxic effects of bivalirudin (an anticoagulant) were evaluated in this intravenous infusion study in Sprague-Dawley rats. Bivalirudin was administered over a 24-hour period by continuous intravenous infusion to six groups of rats. Dose levels of 100, 500, and 2000 mg/kg/24 h were selected for the low-, mid-, and high-dose groups. Three bivalirudin-treated groups of 12 males and 12 females each were designated for toxicology assessment. Six animals/sex/group were euthanized at the completion of 24-hour infusion, and the remaining animals were assigned to a 14-day recovery period. Three additional groups of 10 rats/sex/group were designated for toxicokinetic assessment. This study included a saline control group and a vehicle control group. No bivalirudinrelated toxicity was noted. There were no treatment-related effects on clinical pathology parameters. No definitive test article-related macroscopic, organ weight, or microscopic changes were identified. Three animals in the 500-mg/kg/24 h group, and 7 animals in the 2000-mg/kg/24 h group in the toxicokinetic assessment phase of the study were found dead or euthanized in extremis (following blood sampling). The concurrent clinical signs suggest that the animals hemorrhaged, which is consistent with the pharmacological action of bivalirudin. The extent of systemic exposure was similar in male and female rats, indicating a lack of a sex-related difference. Plasma concentrations of bivalirudin appeared to be linear and dose independent. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) for bivalirudin, administered to rats via intravenous infusion over a 24-hour period, was 2000 mg/kg/24 h. However, the known pharmacological properties of bivalirudin could result in hemorrhage in the presence of an appropriate challenge (e.g., blood collection).
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1091-5818 1092-874X
DOI:	10.1080/10915810305102