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

被引:39
作者
Dansirikul, Chantaratsamon [1 ]
Lehr, Thorsten [1 ]
Liesenfeld, Karl-Heinz [1 ]
Haertter, Sebastian [1 ]
Staab, Alexander [1 ]
机构
[1] Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med, D-88397 Biberach, Germany
关键词
Dabigatran etexilate; NONMEM; pharmacometrics; population pharmacokinetics / pharmacodynamics; thrombin inhibitor; THROMBIN INHIBITOR DABIGATRAN; ORAL DIRECT THROMBIN; POPULATION PHARMACOKINETIC ANALYSIS; TOTAL HIP-REPLACEMENT; PHARMACODYNAMICS; WARFARIN; PERFORMANCE; METABOLISM; SAFETY;
D O I
10.1160/TH11-09-0656
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (05), 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 dabigatran 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.
引用
收藏
页码:775 / 785
页数:11
相关论文
共 33 条
  • [1] NEW LOOK AT STATISTICAL-MODEL IDENTIFICATION
    AKAIKE, H
    [J]. IEEE TRANSACTIONS ON AUTOMATIC CONTROL, 1974, AC19 (06) : 716 - 723
  • [2] Beal S L., 1998, NONMEM Users Guides
  • [3] The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans
    Blech, Stefan
    Ebner, Thomas
    Ludwig-Schwellinger, Eva
    Stangier, Joachim
    Roth, Willy
    [J]. DRUG METABOLISM AND DISPOSITION, 2008, 36 (02) : 386 - 399
  • [4] PREDICTION OF CREATININE CLEARANCE FROM SERUM CREATININE
    COCKCROFT, DW
    GAULT, MH
    [J]. NEPHRON, 1976, 16 (01) : 31 - 41
  • [5] Dabigatran versus Warfarin in Patients with Atrial Fibrillation.
    Connolly, Stuart J.
    Ezekowitz, Michael D.
    Yusuf, Salim
    Eikelboom, John
    Oldgren, Jonas
    Parekh, Amit
    Pogue, Janice
    Reilly, Paul A.
    Themeles, Ellison
    Varrone, Jeanne
    Wang, Susan
    Alings, Marco
    Xavier, Denis
    Zhu, Jun
    Diaz, Rafael
    Lewis, Basil S.
    Darius, Harald
    Diener, Hans-Christoph
    Joyner, Campbell D.
    Wallentin, Lars
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (12) : 1139 - 1151
  • [6] Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II) A randomised, double-blind, non-inferiority trial
    Eriksson, Bengt I.
    Dahl, Ola E.
    Huo, Michael H.
    Kurth, Andreas A.
    Hantel, Stefan
    Hermansson, Karin
    Schnee, Janet M.
    Friedman, Richard J.
    [J]. THROMBOSIS AND HAEMOSTASIS, 2011, 105 (04) : 721 - 729
  • [7] Comparative Pharmacodynamics and Pharmacokinetics of Oral Direct Thrombin and Factor Xa Inhibitors in Development
    Eriksson, Bengt I.
    Quinla, Datfiel J.
    Weitz, Jeffrey I.
    [J]. CLINICAL PHARMACOKINETICS, 2009, 48 (01) : 1 - 22
  • [8] Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement:: BISTRO I
    Eriksson, BI
    Dahl, OE
    Ahnfelt, L
    Kälebo, P
    Stangier, J
    Nehmiz, G
    Hermansson, K
    Kohlbrenner, V
    [J]. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2004, 2 (09) : 1573 - 1580
  • [9] Stability and performance of a population pharmacokinetic model
    Ette, EI
    [J]. JOURNAL OF CLINICAL PHARMACOLOGY, 1997, 37 (06) : 486 - 495
  • [10] Dabigatran with or without concomitant Aspirin compared with Warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study)
    Ezekowitz, Michael D.
    Reilly, Paul A.
    Nehmiz, Gerhard
    Simmers, Timothy A.
    Nagarakanti, Rangadham
    Parcham-Azad, Kambiz
    Pedersen, K. Erik
    Lionetti, Dominick A.
    Stangier, Joachim
    Wallentin, Lars
    [J]. AMERICAN JOURNAL OF CARDIOLOGY, 2007, 100 (09) : 1419 - 1426