title: Predicting dosing advantages of factor VIIa variants with altered tissue factor-dependent and lipid-dependent activities.
abstract: BACKGROUND
  Recombinant factor VIIa (rFVIIa) 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 rFVIIa remain poorly understood, genetic or chemical modifications of rFVIIa have been proposed, with the goal of achieving faster and longer hemostatic action. No ongoing trial is currently comparing rFVIIa variants with each other.
  
  
  OBJECTIVE
  We used mathematical modeling to compare the pharmacokinetics, dose-response (pharmacodynamics) and dose-effect duration (pharmacokinetics/pharmacodynamics) of rFVIIa 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 rFVIIa 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 rFVIIa 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 rFVIIa. The duration of the simulated hemostatic effect after a single optimal dose was prolonged for rFVIIa variants with increased TF affinity or extended half-lives, but not for those with modulated PL activity.
  
  
  CONCLUSIONS
  Some modifications of the rFVIIa molecule may not translate into a prolonged hemostatic effect.
authors.affiliation: Center for Theoretical Problems of Physicochemical Pharmacology RAS, Moscow, Russia.
authors.forename: A M
authors.initials: AM
authors.lastname: Shibeko
authors.forename: S A
authors.initials: SA
authors.lastname: Woodle
authors.forename: I
authors.initials: I
authors.lastname: Mahmood
authors.forename: N
authors.initials: N
authors.lastname: Jain
authors.forename: M V
authors.initials: MV
authors.lastname: Ovanesov
mesh_terms: D015942:Factor VIIa / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008055:Lipids / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D013925:Thromboplastin / Q000502:physiology*
chemical_list: D008055:Lipids; D011994:Recombinant Proteins; D013925:Thromboplastin; D015942:Factor VIIa
keywords: factor VIIa; hemophilia; pharmacology; thrombin; thromboplastin