Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease

Abstract

Aims: The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease.

Methods: Data from five phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non-Q-wave myocardial infarction were evaluated. A total of 3296 pairs of concentration-APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT.

Results: The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically significant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and Emax model. A significant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method-dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and Emax, in the model. For the typical healthy subject and patient, the method-corrected population mean parameters were: APTTbaseline 35 and 31 s, slope 8.0 and 5.8 s x l x micromol(-1), Emax 36 and 34 s, and EC50 0.54 and 0.72 micromol x l(-1), respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 micromol x l(-1) in the healthy volunteer and patient, respectively.

Conclusions: The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and Emax model. Pooling of data was made possible by incorporating a centre-specific characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects.

Figure 1

Mean (± s.d. where applicable) APTT vs time curves. The doses are expressed for a 70 kg person when dosed per kg.

Figure 2

Combined linear and E_max models (solid lines), fitted to pooled data from healthy volunteers (circles) and patients with coronary arterial disease (triangles). Models without covariates.

Figure 3

Model predicted APTT (left panel) and APTT-ratio (right panel) vs inogatran plasma concentration in a typical patient and healthy subject at varying lower limits of the reference range (RefLow).