title: A dose-response study in animals to evaluate the anticoagulant effect of the stage 2 unfractionated heparin USP monograph change.
abstract: The United States Pharmacopeia (USP) monograph for unfractionated heparin (UFH) was revised in October 2009. This revision was anticipated, based upon in vitro tests, to reduce UFH potency by approximately 10%. To study the potential in vivo consequences of the monograph change, we evaluated activated partial thromboplastin time (aPTT) and activated clotting time (ACT) responses in animals. Female mini-pigs and monkeys (n=8/species) were administered intravenously 60, 54, 48, or 42 U/kg and 50, 45, 40, or 35 U/kg "old" (pre-USP revision) UFH, respectively, in a Williams 4×4 crossover design. Blood samples for aPTT and ACT were collected at 15 min after dosing. The same study design was then repeated using "new" (post-USP revision) UFH. Mean "new" UFH aPTT and ACT values were generally lower than those for "old" UFH although individual animal responses varied considerably. The aPTT and ACT response was generally dose-proportional for both "old" and "new" UFH. These studies indicate that the USP monograph alteration for UFH may result in a modest reduction in the anticoagulant response across a population, but the variability in animal responses underscores the importance of individualization of clinical UFH dosing and the importance of anticoagulant test monitoring.
authors.affiliation: Division of Medical Imaging Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. ronald.honchel@fda.hhs.gov
authors.forename: R
authors.initials: R
authors.lastname: Honchel
authors.forename: J
authors.initials: J
authors.lastname: Carraway
authors.forename: N
authors.initials: N
authors.lastname: Gopee
authors.forename: R
authors.initials: R
authors.lastname: Callicott
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Patton
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.forename: J
authors.initials: J
authors.lastname: Zalkkar
authors.forename: A
authors.initials: A
authors.lastname: Laniyonu
authors.forename: I
authors.initials: I
authors.lastname: Krefting
authors.forename: M
authors.initials: M
authors.lastname: Cato
authors.forename: K
authors.initials: K
authors.lastname: Robie-Suh
authors.forename: R
authors.initials: R
authors.lastname: Rieves
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology* / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D000882:Haplorhini; D006493:Heparin / Q000494:pharmacology* / Q000633:toxicity; D010314:Partial Thromboplastin Time / Q000379:methods; D013552:Swine; D014481:United States; D014914:Whole Blood Coagulation Time / Q000379:methods
chemical_list: D000925:Anticoagulants; D006493:Heparin