Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial: a rebuttal

Abstract

See also Liesenfled K‐H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, EzekowitzMD, Yusuf S,Wallentin L, Haertter S, Staab A. 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; 9: 2168–75; and Liesenfeld K‐H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with on‐valvular atrial fibrillation from the RE‐LY trial: reply to a rebuttal. This issue, pp 502–4.

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial: reply to a rebuttal

“…Overall we do not agree with the comments by Patel et al. [1] and consider the model presented as an appropriate and comprehensive representation of the data.…”

“…In our dataset for example only 0.4% of the concentrations were ≥ 500 ng mL −1 , which is presumably the concentration range Patel et al. [1] were referring to. To avoid model misspecification, observed vs. predicted values were fitted using a LOESS smooth function as implemented in the X pose software package [11] throughout the model development.…”

“…In their rebuttal, Patel et al. [1] raised concerns that the relationship between body weight and dabigatran clearance was not thoroughly investigated. In the two large population PK analyzes reported, renal function expressed by creatinine clearance (CRCL, calculated by Cockroft–Gault [3]) was identified consistently as by far the most significant factor in the clearance of dabigatran [2,4].…”

“…Patel et al. [1] raised further concerns that prior knowledge was used to develop the population PK model for the RE‐LY population. It was suggested to build the model solely based on the large data set provided from the RE‐LY trial.…”

“…Furthermore, Patel et al. [1] commented on the goodness‐of‐fit plot displaying some bias. It has to be noted that goodness‐of‐fit plots are very useful tools for model evaluation and selection.…”