Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate

Thrombosis and Haemostasis

Volumn 107, Issue 2, 2012, Pages 260-269

  Härtter, Sebastian ^a   Yamamura, Norio ^a   Stangier, Joachim ^a   Reilly, Paul A ^b   Clemens, Andreas ^a  

^a BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^b BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

Dabigatran; Ethnic origin; Japanese; Pharmacodynamics; Pharmacokinetics

Indexed keywords

DABIGATRAN ETEXILATE; ECARIN;

ADULT; AREA UNDER THE CURVE; ARTICLE; BODY WEIGHT; CAUCASIAN; COAGULATION; ETHNIC DIFFERENCE; FEMALE; HEART ATRIUM FIBRILLATION; HIP ARTHROPLASTY; HUMAN; INTERNATIONAL NORMALIZED RATIO; JAPANESE; KIDNEY CLEARANCE; KNEE ARTHROPLASTY; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; ORTHOPEDIC SURGERY; PARTIAL THROMBOPLASTIN TIME; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTHROMBIN TIME; SINGLE DRUG DOSE; STEADY STATE; STROKE; THROMBIN TIME;

ADMINISTRATION, ORAL; ADULT; ANTICOAGULANTS; ARTHROPLASTY, REPLACEMENT, HIP; ARTHROPLASTY, REPLACEMENT, KNEE; ASIAN CONTINENTAL ANCESTRY GROUP; ATRIAL FIBRILLATION; BENZIMIDAZOLES; CLINICAL TRIALS, PHASE I AS TOPIC; CLINICAL TRIALS, PHASE II AS TOPIC; EUROPEAN CONTINENTAL ANCESTRY GROUP; FEMALE; HUMANS; MALE; POSTOPERATIVE COMPLICATIONS; PYRIDINES; THROMBOSIS;

EID: 84856675273     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1160/TH11-08-0551     Document Type: Article

References (44)

1. Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther 2008; 84: 417-423.
2. Kamali F, Wynne H. Pharmacogenetics of warfarin. Annu Rev Med 2010; 61: 63-75.
3. Kroetz DL, Pauli-Magnus C, Hodges LM, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13: 481-494.
4. Kimchi-Sarfaty C, Marple AH, Shinar S, et al. Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene. Pharmacogenomics 2007; 8: 29-39.
5. Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: A pooled analysis of three trials. Thromb Res 2010; 126: 175-182.
6. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105: 721-729.
7. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
9. Ebner T, Wagner K, Wienen W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos 2010; 38: 1567-1575.
10. Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
11. Tomimori H, Yamamura N, Adachi T. Safety, pharmacokinetics and pharmacodynamics after single rising oral doses of 50, 150 and 350 mg BIBR 1048 MS as capsules in healthy subjects of Japanese and Caucasian origin. Double-blind, randomised, placebo-controlled study. Study 1160.28. Report no. U05-3052. Boehringer Ingelheim Internal Report, 2005.
12. Tomimori H, Yamamura N, Adachi T. Safety, pharmacokinetics and pharmacodynamics after single (150 mg, 220 mg and 300 mg) and multiple (150 mg and 220 mg q.d. and 150 mg b.i.d.) rising oral doses of BIBR 1048 MS/capsules in healthy male subjects of Japanese and Caucasian origin. An Open-label study. Study No. 1160.29. Report no. U06-3091. Boehringer Ingelheim Internal Report, 2006.
13. Rathgen K, Stangier J, Stähle H, et al. Bioavailability of BIBR 953 ZW after 150 mg of BIBR 1048 (oral pro-drug of BIBR 953 ZW) administered as HPMC polymorph II capsule relative to 150 mg HPMC polymorph I capsule in healthy subjects. A two-way, crossover, randomised, open-label trial. Study no. 1160.52. Report no. U05-1125. Boehringer Ingelheim Internal Report, 2005.
14. Tomimori H, Yamamura N, Adachi T, et al. Pharmacokinetics, safety and pharmacodynamics after multiple oral doses of dabigatran etexilate capsule (110 mg and 150 mg b.i.d., 7 days) in healthy Japanese and Caucasian male subjects: An openlabel study. Study no. 1160.61. Report no. U06-3420. Boehringer Ingelheim Internal Report, 2006.
15. Yamamura N, Urano Y, Adachi T. Safety, pharmacokinetics and pharmacodynamics after multiple oral doses of BIBR 1048 MS capsule (150 mg b.i.d., 7 days) in healthy Japanese male subjects. An open-label study. Study no.1160.55. Report no. U05-3334. Boehringer Ingelheim Internal Report, 2005.
16. Stangier J, Stähle H, Rathgen K, et al. Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and diclofenac has little impact on the pharmacokinetics of either drug (abstract). J Thromb Haemost 2007; 5 (Suppl 2): PT677.
17. Jaehnig P, Stähle H, Reseski K, et al. Relative bioavailability of dabigatran and amiodarone after multiple oral administrations of 150 mg dabigatran etexilate b.i.d. with or without 600 mg amiodarone as single dose in healthy male and female volunteers. An open-label, multiple-dose, group-comparison study. Study no.1160.57. Report no. U06-1610, Boehringer Ingelheim Internal Report, 2005.
18. Stangier J, Rathgen K, Stähle H, et al. Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmacodynamics.Am J Cardiovasc Drugs 2009; 9: 59-68.
19. Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, with coadministration of digoxin. J Clin Pharmacol 2011; epub ahead of print.
20. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45: 555-563.
21. Rathgen K, Stähle H, Stangier J. Bioavailability of BIBR 953 ZW after 150 mg of BIBR 1048 (oral prodrug of BIBR 953 ZW) administered as HPMC capsule relative to a gelatine capsule, and bioavailability of the HPMC capsule under the influence of food in healthy subjects. A three-way crossover, randomised, openlabel trial. Study no. 1160.40. Report no. U04-1459-01. Boehringer Ingelheim Internal Report, 2005.
22. Ring A, Clemens A, Rathgen K, et al. Dabigatran does not prolong the QTc interval with supratherapeutic exposure: A thorough QTc study (abstract). J Am Coll Cardiol 2011; 57 (14 Suppl 1): E56.
23. Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49: 259-268.
24. 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.
25. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular AF (PETRO Study). Am J Cardiol 2007; 100: 1419-1426.
26. Tomimori H, Yamamura N, Adachi T. Open label, randomized, exploratory, dose response study of the pharmacodynamics and safety of BIBR 1048 (110 mg b.i.d. and 150 mg b.i.d.) for 12 weeks in patients with non-valvular AF in comparison towarfarin. Study no.1160.49. Report no. U07-3126. Boehringer Ingelheim Internal Report, 2007.
27. Eriksson BI, Dahl OE, Büller HR, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 3: 103-111.
28. Fuji T, Fuijita S, Ujihira T, et al. Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients, with a safety profile comparable to placebo. J Arthroplasty 2010; 25: 1267-1274.
29. Boehringer Ingelheim. Advisory Committee Briefing Document. Available at: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterialsDrugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM226009.pdf. Accessed Aug 9, 2011.
30. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP) Assessment Report for Pradaxa. 9 June 2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_ Variation/human/000829/WC500110875.pdf. Accessed Sept 13, 2011.
31. Stangier J, Rathgen K, Stähle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
32. Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47-59.
33. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5: 2178-2185.
34. Hori M, Connolly SJ, Ezekowitz MD, et al. Efficacy and safety of dabigatran vs.warfarin in patients with atrial fibrillation. Circ J 2011; 75: 800-805.
35. U.S. Food and Drug Administration - Briefing Information, Dabigatran Etexilate Mesylate Capsules, for the September 20, 2010 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM247244.pdf Accessed Aug 9, 2011.
36. Johansson LC, Andersson M, Fager G, et al. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers. Clin Pharmacokinet 2003; 42: 475-484.
37. Wernevik LC, Nystrom P, Andersson M, et al. Comparable pharmacokinetics and pharmacodynamics of melagatran in Japanese and Caucasian volunteers after oral administration of the direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2006; 45: 85-94.
38. Bjornsson TD, Wagner JA, Donahue SR, et al. A review and assessment of potential sources of ethnic differences in drug responsiveness. J Clin Pharmacol 2003; 43: 943-967.
39. ® Prescribing Information. Available at: http://www.pradaxa.com/ Accessed Aug 9, 2011.
40. Health Canada. Health Canada - Pradax™ Prescribing Information. Oct 26th, 2010.
41. ® Package Insert. Available at: http://www.info.pmda.go.jp/downfiles/ph/PDF/650168_3339001M1024_1_04.pdf Accessed Oct 3, 2011.
42. European Medicines Agency. Pradaxa. Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf. Accessed Sept 13, 2011.
43. Therapeutic Goods Administration. Australian Public Assessment Report for Dabigatran etexilate mesilate. Available at: http://www.tga.gov.au/pdf/auspar/auspar-pradaxa.pdf Accessed Aug 9, 2011.
44. Troconiz IF, Tillmann C, Liesenfeld KH, et al. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patientsundergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007; 47: 371-382.