Subscribe to RSS
A Pharmacokinetic Evaluation of Dabigatran Etexilate, Total Dabigatran, and Unconjugated Dabigatran Following the Administration of Dabigatran Etexilate Mesylate Capsules in Healthy Male and Female Subjects
received 14 May 2019
accepted 01 October 2019
25 October 2019 (online)
Purpose Due to bioanalytical limitations it was previously not possible to evaluate the pharmacokinetics of dabigatran etexilate. We have developed validated methods to assay dabigatran etexilate, unconjugated dabigatran, and total dabigatran that will allow for a complete investigation into the pharmacokinetics of dabigatran etexilate mesylate. This study was designed to evaluate the pharmacokinetics of these analytes in healthy subjects.
Methods This was an open-label, single-dose, one-period, one-treatment study. A single oral dose of dabigatran etexilate mesylate capsule containing the equivalent of 150 mg dabigatran etexilate was administered to each subject. A total of 23 blood samples for pharmacokinetic analysis were collected and analyzed from each subject. Safety and tolerability were monitored throughout the study.
Results Eighteen healthy subjects were enrolled, dosed, and completed the study. The dabigatran etexilate mean Cmax was 6.9±5.63 ng/mL, the median Tmax was 0.67 h (range=0.50–1.00 h), the mean AUCt was 5.32±4.82 ng/mL·h, the mean AUCinf was 5.36±4.83 pg/mL*h, and the mean t1/2 was 0.54±0.26 h. Only one subject experienced an adverse event.
Conclusion Using validated bioanalytical methods, a complete characterization of dabigatran etexilate, total dabigatran, and unconjugated dabigatran pharmacokinetics was achieved. Advancements in the development of new more accurate, specific, and sensitive validated bioanalytical methods such as these enable for a complete understanding of the drug’s pharmacokinetics and this, in turn, can have an impact on both the drug development and the evaluation of generic formulations.
- 1 January CT, Wann LS, Alpert JS. et al. ACC/AHA Task Force Members 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130 (23) 2071-2104. doi: https://doi.org/10.1161/CIR.0000000000000041
- 2 Kirchhof P, Benussi S, Kotecha D. et al. ESC Scientific Document Group 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37: 2893-2962. doi: https://doi.org/10.1093/eurheartj/ehw210
- 3 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149: 315-352. doi: https://doi.org/10.1016/j.chest.2015.11.026
- 4 Becattini C, Agnelli G. Treatment of venous thromboembolism with new anticoagulant agents. J Am Coll Cardiol 2016; 67: 1941-1955 doi: https://doi.org/10.1016/j.jacc.2016.01.072
- 5 Ganetsky M, Babu KM, Salhanick SD, Brown RS. et al. Dabigatran: Review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol 2011; 7: 281-287. doi: https://doi.org/10.1007/s13181-011-0178-y
- 6 Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol 2011; 72: 581-592 doi: https://doi.org/10.1111/j.1365-2125.2011.03916.x
- 7 Stangier J, Stähle H, Rathgen K. et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol 2008; 48: 1411-1419. doi: https://doi.org/10.1177/0091270008324179
- 8 Boehringer Ingelheim Pharmaceuticals, Inc (2018) Highlights of prescribing information: Pradaxa (dabigatran etexilate mesylate) capsules, for oral use https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022512s035lbl.pdf Accessed 9 September 2019
- 9 Food and Drug Administration Office of Generic Drugs (2017) Draft guidance on dabigatran etexilate mesylate. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM308030.pdf Accessed 9 September 2019
- 10 European Medicines Agency: Committee for Medicinal Products for Human Use (CHMP) (2016) Dabigatran etexilate, hard capsules, 75 mg, 110 mg and 4 150 mg product-specific bioequivalence guidance (EMA/CHMP/805498/2016) https://www.ema.europa.eu/en/documents/scientific-guideline/dabigatran-etexilate-hard-capsule-75-mg-110-mg-150-mg-product-specific-bioequivalence-guidance_en.pdf Accessed 9 September 2019
- 11 Boehringer Ingelheim International GmbH (2017) Summary of product characteristics: pradaxa 75 mg, 110 mg, 150 mg hard capsules http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000829/human_med_000981.jsp&mid=WC0b01ac058001d124 Accessed 9 September 2019
- 12 Urooj F, Kulkarni A, Stapleton D. et al. New oral anticoagulants in nonvalvular atrial fibrillation. Clin Cardiol 2016; 39: 739-746. doi: https://doi.org/10.1002/clc.22582
- 13 Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J 28 2013; 11: 10. doi: https://doi.org/10.1186/1477-9560-11-10
- 14 Orange Book: approved drug products with therapeutic equivalence evaluations https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm Accessed 10 April 2018
- 15 Boehringer Ingelheim. Advisory Committee Briefing Document. Document Date: 27 Aug 2010. Stroke_prevention_in_atrial_fibrillation_established_oral_anticoagulants_versus_novel_anticoagulants-translating_clinical_trial_data_into_practice. https://www.researchgate.net/publication/262733892 Accessed 01 May 2018
- 16 Li J, Fang J, Zhong F. et al. Development and validation of a liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of dabigatran etexilate, intermediate metabolite and dabigatran in 50 µL rat plasma and its application to pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 973: 110-119 doi: https://doi.org/10.1016/j.jchromb.2014.09.025
- 17 Nouman EG, Al-Ghobashy MA, Lotfy HM. Development and validation of LC–MSMS assay for the determination of the prodrug dabigatran etexilate and its active metabolites inhuman plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2015; 989: 37-45. doi: https://doi.org/10.1016/j.jchromb.2015.02.042
- 18 Baglin T, Hillarp A, Tripodi A. et al. Measuring oral direct inhibitors of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013; 11: 756-760. doi: https://doi.org/10.1111/jth.12149
- 19 Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 2013; 29 (7 Suppl) S24-S33. doi: https://doi.org/10.1016/j.cjca.2013.04.002
- 20 Reilly PA, Lehr T, Haertter S. et al. RE-LY Investigators (2014) The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 63: 321-328. doi: https://doi.org/10.1016/j.jacc.2013.07.104
- 21 Food and Drug Administration: Center for Drug Evaluation and Research (2010) Application number 22-512: summary review https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000SumR.pdf Accessed 9 September 2019