title: Pharmacodynamic considerations in the selection of dosage of tinzaparin for various indications: experimental studies in primates.
abstract: Like unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs) are polypharmacologic agents that can modulate the hemostatic system at multiple points. Thus, to select an optimal dose of LMWH for a given indication, it is necessary to consider multiple actions of the drug. In this study, nonhuman primates were treated with intravenous or subcutaneous boluses of the LMWH tinzaparin or UFH. Doses were selected on the basis of the expected prophylactic (75 U/kg) and therapeutic (175 U/kg) dosing of tinzaparin. Blood samples were drawn periodically up to 24 hours after administration. Circulating anti-Xa and anti-thrombin (anti-IIa) activities determined using amidolytic assays were used to estimate plasma tinzaparin (heparin) concentrations. In addition, total tissue factor pathway inhibitor (TFPI) levels were measured in these primates. Subcutaneous administration of 75 U/kg tinzaparin resulted in plasma levels of approximately 0.2 to 0.3 U/mL, concentrations sufficient for DVT prophylaxis. Such drug levels were not associated with a significant release of TFPI. Intravenous administration of the same dose resulted in a peak drug level of approximately 1.5 anti-Xa U/mL. The elimination half-life was approximately 1 hour. Thus, intravenously administered tinzaparin may be useful for providing anticoagulation during coronary interventions. Subcutaneous administration of 175 U/kg resulted in tinzaparin levels of approximately 0.7 anti-Xa U/mL and a significant increase in TFPI levels. Interestingly, the increase in TFPI levels occurred over a different time frame than anticoagulant activity. Intravenous administration of 175 U/kg resulted in peak drug concentrations of almost 5 anti-Xa U/mL. The pharmacokinetic behavior of intravenously administered tinzaparin was comparable to that of UFH. The data show that the pharmacokinetic and pharmacodynamic effects measured using different assays widely differ. For a proper pharmacodynamic analysis, multiple assays should be considered, given that both UFH and LMWHs are polycomponent in nature.
authors.affiliation: Cardiovascular Institute, Loyola University Medical Center, Maywood, Illinois, USA. wjeske@lumc.edu
authors.forename: Walter
authors.initials: W
authors.lastname: Jeske
authors.forename: Jawed
authors.initials: J
authors.lastname: Fareed
mesh_terms: D000818:Animals; D001682:Biological Availability; D065427:Factor Xa Inhibitors; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D010599:Pharmacokinetics; D011516:Prothrombin / Q000037:antagonists & inhibitors; D000078222:Tinzaparin
chemical_list: D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin; D011516:Prothrombin; C025337:Factor IIa