Marie Cullberg1), Ulf Eriksson1), Mats Karlsson2)
1)Experimental Medicine, Astra Hässle, Sweden; 2)Department of Pharmacy, Uppsala University, Sweden
Aim: The aim of the present analysis was to characterize the relationship between the plasma concentration of inogatran, a synthetic low molecular weight thrombin inhibitor intended for prophylaxis and treatment of thrombosis, and APTT (Activated Partial Thromboplastin Time), a measure used to assess the degree of anticoagulation, in healthy volunteers and patients with coronary arterial disease.
Data and Methods: Data from seven clinical phase I-II studies in a total of 1027 individuals (78 healthy subjects and 953 patients) was included in the analysis. A total of 3296 pairs of blood samples were drawn for subsequent determination of inogatran concentration and APTT in plasma. APTT was determined according to the standard method of the local laboratory having varying reference ranges, which were characterized by the lower, upper and midpoint values as well as the width of the range. Different pharmaco-dynamic models were compared using Nonlinear Mixed Effects Modelling (NONMEM V).
Results and Conclusion: A non-linear concentration-dependent prolongation of APTT was observed, which was best described by a combined linear and Emax model:
APTT = APTTbaseline + COEFF · C + Emax · C/(EC50+ C).
Patients seemed to have lower APTTbaseline and less pronounced effect (lower COEFF) of inogatran than healthy volunteers. In addition, a significant part of the variability in APTT could be ascribed to the method, the lower reference value of the normal range being the most explanatory covariate on APTTbaseline and Emax. Other covariates tested, but not significantly (p>0.0001) influencing the APTT-concentration relationship, were diagnosis (p<0.05), age (p<0.005), gender, weight, smoking habits, concomitant diseases and ASA-medication. The results from this investigation demonstrates that it is important to relate the APTT values to the reference range of the method used, when pooling results from several studies and/or study centers.
Reference: PAGE 8 (1999) Abstr 146 [www.page-meeting.org/?abstract=146]
Poster: poster