A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery

 

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Summary

Dabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct thrombin inhibitor. Using data from eight clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing orthopaedic surgery (OS), population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to investigate whether the PK and PD of dabigatran differ across different populations. In both healthy volunteers (n=80) and patients (n=1,965), the PK of dabigatran was best described by a two-compartment disposition model with first-order absorption and elimination. Renal function was the only covariate shown to have a clinically relevant impact on dabig-atran exposure. The patient PK model was successfully applied in predicting exposure observed in the RE-LY trial evaluating dabigatran treatment in patients with non-valvular AF. The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (E_max) model, consistent with previous reports. PK/PD relationships were robust across the various populations tested and were not affected by any of the covariates examined. In summary, the PK of dabigatran is sufficiently consistent to allow extrapolation of data generated in healthy volunteers to patients with AF or undergoing OS.

• References

• 1 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.
  CrossrefPubMedGoogle Scholar
• 2 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 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.
  CrossrefPubMedGoogle Scholar
• 4 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
  CrossrefPubMedGoogle Scholar
• 5 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.
  CrossrefPubMedGoogle Scholar
• 6 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
  CrossrefPubMedGoogle Scholar
• 7 Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47-59.
  CrossrefPubMedGoogle Scholar
• 8 Liesenfeld KH, Schafer HG, Troconiz IF. et al. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006; 62: 527-537.
  CrossrefPubMedGoogle Scholar
• 9 Troconiz IF, Tillmann C, Liesenfeld KH. et al. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007; 47: 371-382.
  CrossrefPubMedGoogle Scholar
• 10 Rathgen K, Stangier J, Stähle H, Jungnik A. 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
  PubMedGoogle Scholar
• 11 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; 09: 59-68.
  CrossrefPubMedGoogle Scholar
• 12 Stangier J, Rathgen K, Stähle H, Mazur D. 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.
  CrossrefPubMedGoogle Scholar
• 13 Eriksson BI, Dahl OE, Buller HR. et al. A new oral direct thrombin inhibitor, da-bigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 03: 103-111.
  CrossrefPubMedGoogle Scholar
• 14 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 atrial fibrillation in comparison to warfarin. Study no.1160.49. Report no. U07-3126. Boehringer Ingelheim Internal Report. 2007
  PubMedGoogle Scholar
• 15 Ezekowitz MD, Reilly PA, Nehmiz G. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100: 1419-1426.
  CrossrefPubMedGoogle Scholar
• 16 Tomimori H, Yamamura N, Adachi T, Fukui K. 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 open label study. Study no. 1160.61. Report no. U06-3420. Boehringer Ingelheim Internal Report. 2006
  PubMedGoogle Scholar
• 17 Eriksson BI, Dahl OE, Ahnfelt L. et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004; 02: 1573-1580.
  CrossrefPubMedGoogle Scholar
• 18 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.
  CrossrefPubMedGoogle Scholar
• 19 Jonsson EN, Karlsson MO. Xpose--an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999; 58: 51-64.
  CrossrefPubMedGoogle Scholar
• 20 Akaike H. A new look at the statistical model identification. IEEE Trans Automatic Control 1974; 19: 716-723.
  CrossrefPubMedGoogle Scholar
• 21 Beal SL, Sheiner LB. NONMEM Users Guides. San Francisco: NONMEM Project Group University of California; 1998
  Google Scholar
• 22 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
  CrossrefPubMedGoogle Scholar
• 23 Ette EI. Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 1997; 37: 486-495.
  CrossrefPubMedGoogle Scholar
• 24 Parke J, Holford NH, Charles BG. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed 1999; 59: 19-29.
  CrossrefPubMedGoogle Scholar
• 25 Post TM, Freijer JI, Ploeger BA, Danhof M. Extensions to the visual predictive check to facilitate model performance evaluation. J Pharmacokinet Pharmacodyn 2008; 35: 185-202.
  CrossrefPubMedGoogle Scholar
• 26 Liesenfeld KH, Lehr T, Dansirikul C. et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 09: 2168-2175.
  CrossrefPubMedGoogle Scholar
• 27 Yuen GJ. Altered pharmacokinetics in the elderly. Clin Geriatr Med 1990; 06: 257-267.
  PubMedGoogle Scholar
• 28 Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003; 38: 843-853.
  CrossrefPubMedGoogle Scholar
• 29 Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009; 41: 67-76.
  CrossrefPubMedGoogle Scholar
• 30 Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet 2003; 42: 107-121.
  CrossrefPubMedGoogle Scholar
• 31 Haertter S, Yamamura N, Stangier J. et al. Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate. Thromb Haemost 2012; 107: 260-269.
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Boehringer Ingelheim. Advisory Committee Briefing Document. Available from: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterialsDrugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM226009.pdf Accessed, 23rd November 2011.
  PubMedGoogle Scholar
• 33 Reilly PA, Conrad CA, Faaij RA. et al. Concomitant use of P-glycoprotein inhibitors with dabigatran or warfarin in the RE-LY trial (abstract 129). Eur Heart J 2011; 32 (Suppl. 01) 6.
  PubMedGoogle Scholar
• 34 Lehr T, Haertter S, Liesenfeld KH. et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: Dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol. 2011 epub ahead of print.
  PubMedGoogle Scholar
• 35 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate - a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
  Article in Thieme ConnectPubMedGoogle Scholar
• 36 Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48: 1-22.
  CrossrefPubMedGoogle Scholar
• 37 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103: 572-585.
  Article in Thieme ConnectPubMedGoogle Scholar

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