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 ®ve 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 signi®cant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and E max model. A signi®cant 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 E max , in the model. For the typical healthy subject and patient, the method-corrected population mean parameters were: APTT baseline 35 and 31 s, slope 8.0 and 5.8 s l mmol x1 , E max 36 and 34 s, and EC 50 0.54 and 0.72 mmol l x1 , respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 mmol l x1 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 E max model. Pooling of data was made possible by incorporating a centre-speci®c 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.

Pharmacokinetic/Pharmacodynamic Relationships for Otamixaban, a Direct Factor Xa Inhibitor, in Healthy Subjects

“…For the clinical studies on S18326, a selective thrombin inhibitor, Gaussem et al 6 selected their PD marker (aPTT) based on in vitro linearity and sensitivity, which was confirmed ex vivo in healthy subjects. Cullberg et al 7 described for the thrombin inhibitor inogatran in healthy subjects and coronary artery disease (CAD) patients a combined linear/E max ex vivo model for aPTT, in agreement with in vitro findings.…”

“…Interestingly, this difference in baseline value did not seem to affect HCT response (E max and EC 50 ) to otamixaban. Cullberg et al 7 observed in their population PK/PD model for inogatran differences in E 0 and in E max values for aPTT. The full model identified that E 0 was influenced by age and aPTT method, whereas E max correlated with method and, to some extent, with age and diagnosis.…”

“…In addition, these PK/PD relationships should be well described and understood as they will, in fine , relate to the drug's safety and efficacy 1 . These PK/PD relationships constitute key elements of the final population PK/PD model, where covariates for variability are identified that allow safety and efficacy in the target patient population to be more adequately predicted 5 – 7 …”

“…It may, however, not be relevant to compare anticoagulant effect across drugs, as a same anticoagulant response (ie, 2‐fold change in aPTT) may produce different levels of bleeding and of an antithrombotic effect, based on individual drug properties and mechanisms of action 2 , 7 . In addition, clotting time measurements as biomarkers have some limitations as, pending on the underlying mechanisms, some of them may rather reflect a pure enzyme inhibition than demonstrate real in vivo effect 8 .…”

Fluorescence-Based Blood Coagulation Assay Device for Measuring Activated Partial Thromboplastin Time

“…However, the new test was far more sensitive to actual patient samples. The use of heparin-spiked samples for the purpose of the aPTT reference and therapeutic range establishment has been shown to be misleading 19,42 . It has previously been shown that calibrations based on in vitro heparin addition to pooled plasmas yield a much lower aPTT therapeutic range in comparison to calibrations based on heparintreated patient samples 43 .…”