A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery
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.
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Connolly, Stuart J.
Ezekowitz, Michael D.
论文数: 0引用数: 0
h-index: 0
机构:
Lankenau Inst Med Res, Wynnewood, PA USA
Ctr Heart, Wynnewood, PA USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Ezekowitz, Michael D.
Yusuf, Salim
论文数: 0引用数: 0
h-index: 0
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Yusuf, Salim
论文数: 引用数:
h-index:
机构:
Eikelboom, John
Oldgren, Jonas
论文数: 0引用数: 0
h-index: 0
机构:
Uppsala Clin Res Ctr, Uppsala, SwedenMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Oldgren, Jonas
Parekh, Amit
论文数: 0引用数: 0
h-index: 0
机构:
Lankenau Inst Med Res, Wynnewood, PA USA
Ctr Heart, Wynnewood, PA USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Parekh, Amit
Pogue, Janice
论文数: 0引用数: 0
h-index: 0
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Pogue, Janice
Reilly, Paul A.
论文数: 0引用数: 0
h-index: 0
机构:
Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Reilly, Paul A.
Themeles, Ellison
论文数: 0引用数: 0
h-index: 0
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Themeles, Ellison
Varrone, Jeanne
论文数: 0引用数: 0
h-index: 0
机构:
Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Varrone, Jeanne
Wang, Susan
论文数: 0引用数: 0
h-index: 0
机构:
Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Wang, Susan
Alings, Marco
论文数: 0引用数: 0
h-index: 0
机构:
Working Grp Cardiovasc Res Netherlands, Utrecht, NetherlandsMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Alings, Marco
Xavier, Denis
论文数: 0引用数: 0
h-index: 0
机构:
St Johns Natl Acad Hlth Sci, Bangalore, Karnataka, IndiaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Xavier, Denis
Zhu, Jun
论文数: 0引用数: 0
h-index: 0
机构:
FuWai Hosp, Beijing, Peoples R ChinaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Zhu, Jun
Diaz, Rafael
论文数: 0引用数: 0
h-index: 0
机构:
Estudios Clin Latinoamer, Rosario, Santa Fe, ArgentinaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Diaz, Rafael
Lewis, Basil S.
论文数: 0引用数: 0
h-index: 0
机构:
Lady Davies Carmel Med Ctr, Haifa, IsraelMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Lewis, Basil S.
Darius, Harald
论文数: 0引用数: 0
h-index: 0
机构:
Vivantes Klinikum Neukolln, Berlin, GermanyMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Darius, Harald
Diener, Hans-Christoph
论文数: 0引用数: 0
h-index: 0
机构:
Univ Duisburg Essen, Essen, GermanyMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Diener, Hans-Christoph
Joyner, Campbell D.
论文数: 0引用数: 0
h-index: 0
机构:
Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Joyner, Campbell D.
Wallentin, Lars
论文数: 0引用数: 0
h-index: 0
机构:
Uppsala Clin Res Ctr, Uppsala, SwedenMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Connolly, Stuart J.
Ezekowitz, Michael D.
论文数: 0引用数: 0
h-index: 0
机构:
Lankenau Inst Med Res, Wynnewood, PA USA
Ctr Heart, Wynnewood, PA USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Ezekowitz, Michael D.
Yusuf, Salim
论文数: 0引用数: 0
h-index: 0
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Yusuf, Salim
论文数: 引用数:
h-index:
机构:
Eikelboom, John
Oldgren, Jonas
论文数: 0引用数: 0
h-index: 0
机构:
Uppsala Clin Res Ctr, Uppsala, SwedenMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Oldgren, Jonas
Parekh, Amit
论文数: 0引用数: 0
h-index: 0
机构:
Lankenau Inst Med Res, Wynnewood, PA USA
Ctr Heart, Wynnewood, PA USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Parekh, Amit
Pogue, Janice
论文数: 0引用数: 0
h-index: 0
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Pogue, Janice
Reilly, Paul A.
论文数: 0引用数: 0
h-index: 0
机构:
Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Reilly, Paul A.
Themeles, Ellison
论文数: 0引用数: 0
h-index: 0
机构:
McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Hamilton Hlth Sci, Hamilton, ON, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Themeles, Ellison
Varrone, Jeanne
论文数: 0引用数: 0
h-index: 0
机构:
Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Varrone, Jeanne
Wang, Susan
论文数: 0引用数: 0
h-index: 0
机构:
Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USAMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Wang, Susan
Alings, Marco
论文数: 0引用数: 0
h-index: 0
机构:
Working Grp Cardiovasc Res Netherlands, Utrecht, NetherlandsMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Alings, Marco
Xavier, Denis
论文数: 0引用数: 0
h-index: 0
机构:
St Johns Natl Acad Hlth Sci, Bangalore, Karnataka, IndiaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Xavier, Denis
Zhu, Jun
论文数: 0引用数: 0
h-index: 0
机构:
FuWai Hosp, Beijing, Peoples R ChinaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Zhu, Jun
Diaz, Rafael
论文数: 0引用数: 0
h-index: 0
机构:
Estudios Clin Latinoamer, Rosario, Santa Fe, ArgentinaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Diaz, Rafael
Lewis, Basil S.
论文数: 0引用数: 0
h-index: 0
机构:
Lady Davies Carmel Med Ctr, Haifa, IsraelMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Lewis, Basil S.
Darius, Harald
论文数: 0引用数: 0
h-index: 0
机构:
Vivantes Klinikum Neukolln, Berlin, GermanyMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Darius, Harald
Diener, Hans-Christoph
论文数: 0引用数: 0
h-index: 0
机构:
Univ Duisburg Essen, Essen, GermanyMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Diener, Hans-Christoph
Joyner, Campbell D.
论文数: 0引用数: 0
h-index: 0
机构:
Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, CanadaMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada
Joyner, Campbell D.
Wallentin, Lars
论文数: 0引用数: 0
h-index: 0
机构:
Uppsala Clin Res Ctr, Uppsala, SwedenMcMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada