Jules Heuberger
Centre for Human Drug Research
Objectives: To develop a population PK-PD model to characterize the Factor VIIa concentration-effect relationship for Thrombin Generation Assay with platelets (AUC of peak, TGTp_AUC), activated partial thromboplastin time (aPTT), thromboelastography (MCF: maximum clot firmness) and Prothrombin fragments 1+2 (F1+2). This model was then used to optimize a treatment regimen that is expected to be effective in treating and preventing bleedings in hemophilia A/B patients with inhibitors.
Methods: Data on the administration of 25, 75 and 225 µg/kg LR769 to 15 hemophilia A/B patients from a randomized, open label multiple dose cross-over study were used to develop a PK/PD model. FVIIa activity was assessed by modified STACLOT rTF assay. The identified population PK-PD models were used to simulate the response curves as a function of Factor VIIa activity with different dosing regimens.
Results: A two-compartment model for bolus IV administration was selected for the pharmacokinetics of FVIIa, with lean body mass (LBM) as a covariate on Vd and inter-individual variability on the elimination rate constant. Using the PK model as a driving factor, four PD models were developed for the different PD measurements. A sigmoidal maximal effect model was identified for TGTp_AUC, MCF, F1+2 (increasing with increasing FVIIa) and aPTT (decreasing with increasing FVIIa) with the latter two having a gamma fixed at 1. Also, the effect in F1+2 showed a delayed effect, which was modelled using an effect compartment. Several dose regimens were simulated and evaluated for desired effect levels.
Conclusions: Based on these results, LR769 showed dose responsiveness and two dosing regimens were chosen to be studied in the Phase 3 study: 75µg/kg every 3hrs and 225µg/kg, if needed followed 9 hrs later by 75µg/kg were deemed to have the most optimal effect-profile. Preliminary results of the ongoing Phase 3 study indicate these doses may be effective and safe.
Reference: PAGE 24 () Abstr 3403 [www.page-meeting.org/?abstract=3403]
Poster: Drug/Disease modeling - Other topics