Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran

被引:242
作者
Stangier, Joachim [1 ]
Feuring, Martin [2 ]
机构
[1] Boehringer Ingelheim GmbH & Co KG, Drug Metab & Pharmacokinet, D-88397 Biberach, Germany
[2] Boehringer Ingelheim GmbH & Co KG, Dept Med Affairs, Ingelheim, Germany
关键词
coagulation time; dabigatran concentration measurement; dabigatran etexilate; direct thrombin inhibitor; HEMOCLOT Thrombin Inhibitors assay; Pradaxa; PHARMACODYNAMICS; PHARMACOKINETICS; ETEXILATE;
D O I
10.1097/MBC.0b013e32834f1b0c
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The objective of the present study was to assess the suitability of an accurate, sensitive, standardized, chronometric blood coagulation test to determine the anticoagulation activity of dabigatran and to quantify concentrations of dabigatran in plasma. Dabigatran was spiked at increasing concentrations in pooled citrated normal human plasma to measure diluted thrombin time with the HEMOCLOT THROMBIN INHIBITOR assay. Calibration curve linearity, inter-assay and intra-assay precision, and assay accuracy were investigated. Dabigatran stability in plasma and the feasibility of lyophilized dabigatran standards for assay calibration were assessed. Data are presented as back-calculated plasma concentrations of dabigatran using regression analysis. Dabigatran's calibration curve for thrombin clotting time was linear over the concentration range 0-4000 nmol/l (0-1886 ng/ml). The R-2 was 0.99. Total assay imprecision for dabigatran was 4.7-12.0% coefficient of variation, with 1.2-3.1% for intra-run imprecision, 4.0-10.0% for inter-run precision and 0.3-8.3% for between-day imprecision. Assay accuracy was determined at three dabigatran concentrations; deviation from sample target concentrations ranged from -20.7% (100 nmol/l; 47.15 ng/ml) to 5.6% (1500 nmol/l; 707.3 ng/ml). Assay robustness was determined by analysing identical dabigatran samples in two independent laboratories. The mean bias of dabigatran coagulation times between laboratories was 6.6%. The HEMOCLOT Thrombin Inhibitors assay is suitable for determining the anticoagulant activity and calculating plasma concentrations of dabigatran using simple and widely available chronometric coagulation devices. The use of this rapid, established, standardized and calibrated assay should provide accurate and consistent results when assessing the anticoagulant activity of dabigatran. Blood Coagul Fibrinolysis 23:138-143 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
引用
收藏
页码:138 / 143
页数:6
相关论文
共 10 条
[1]  
Bland JM, 1999, STAT METHODS MED RES, V8, P135, DOI 10.1177/096228029900800204
[2]  
Gardiner C, 2008, H57A NCCLS
[3]   Advances in oral anticoagulants: focus on dabigatran etexilate [J].
Hazlewood, Kathleen A. ;
Weiland, Christy M. .
EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2010, 3 (06) :727-737
[4]  
HYPHEN BioMed, 2009, HYPHEN BIOMED
[5]   Fit-for-purpose method development and validation for successful biomarker measurement [J].
Lee, JW ;
Devanarayan, V ;
Barrett, YC ;
Weiner, R ;
Allinson, J ;
Fountain, S ;
Keller, S ;
Weinryb, I ;
Green, M ;
Duan, L ;
Rogers, JA ;
Millham, R ;
O'Brien, PJ ;
Sailstad, J ;
Khan, M ;
Ray, C ;
Wagner, JA .
PHARMACEUTICAL RESEARCH, 2006, 23 (02) :312-328
[6]   Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects [J].
Stangier, Joachim ;
Staehle, Hildegard ;
Rathgen, Karin ;
Fuhr, Reinhold .
CLINICAL PHARMACOKINETICS, 2008, 47 (01) :47-59
[7]   The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects [J].
Stangier, Joachim ;
Rathgen, Karin ;
Staehle, Hildegard ;
Gansser, Dietmar ;
Roth, Willy .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2007, 64 (03) :292-303
[8]  
Tholen DW, 2004, EP5A2 NCCLS
[9]   Dabigatran etexilate - a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity [J].
van Ryn, Joanne ;
Stangier, Joachim ;
Haertter, Sebastian ;
Liesenfeld, Karl-Heinz ;
Wienen, Wolfgang ;
Feuring, Martin ;
Clemens, Andreas .
THROMBOSIS AND HAEMOSTASIS, 2010, 103 (06) :1116-1127
[10]   New oral anticoagulants in development [J].
Weitz, Jeffrey I. .
THROMBOSIS AND HAEMOSTASIS, 2010, 103 (01) :62-70