Premium
Predicting dosing advantages of factor VII a variants with altered tissue factor‐dependent and lipid‐dependent activities
Author(s) -
Shibeko A. M.,
Woodle S. A.,
Mahmood I.,
Jain N.,
Ovanesov M. V.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12628
Subject(s) - pharmacodynamics , pharmacokinetics , tissue factor , pharmacology , factor viia , ex vivo , factor vii , recombinant factor viia , medicine , dosing , in vivo , coagulation , tissue factor pathway inhibitor , in vitro , chemistry , anesthesia , biochemistry , biology , microbiology and biotechnology
Summary Background Recombinant factor VIIa (r FVII a) is an FX‐cleaving coagulation enzyme licensed for the treatment of bleeding episodes in hemophiliacs with inhibitory antibodies. Even though the optimal dosing and comparative dose efficacy of r FVII a remain poorly understood, genetic or chemical modifications of r FVII a have been proposed, with the goal of achieving faster and longer hemostatic action. No ongoing trial is currently comparing r FVII a variants with each other. Objectives and methods We used mathematical modeling to compare the pharmacokinetics, dose–response (pharmacodynamics) and dose‐effect duration (pharmacokinetics/pharmacodynamics) of rFVII a variants to predict their optimal doses. The pharmacodynamic (PD) model of FXa generation by FVIIa in complexes with tissue factor (TF) and procoagulant lipids (PLs) was validated against published ex vivo and in vitro thrombin generation (TG) experiments. To compare variants' safety profiles, the highest non‐thrombogenic doses were estimated from the clinical evidence reported for the licensed rFVII a product. Results The PD model correctly described the biphasic TF‐dependent and PL‐dependent dose response observed in TG experiments in vitro . The pharmacokinetic/PD simulations agreed with published ex vivo TG data for r FVII a and the BAY 86‐6150 variant, and explained the similar efficacies of a single dose of 270 μg kg −1 (as reported in the literature) and repeated doses of 90 μg kg −1 of unmodified r FVII a. The duration of the simulated hemostatic effect after a single optimal dose was prolonged for r FVII a variants with increased TF affinity or extended half‐lives, but not for those with modulated PL activity. Conclusions Some modifications of the rFVII a molecule may not translate into a prolonged hemostatic effect.