A Population PK/PD Model Assessing The Pharmacodynamics Of A Rapid-Acting Recombinant FVII Analogue, NN1731, In Healthy Male Subjects
Andreas Groth1, Judi Møss2, Tine Møller3, Steen Ingwersen1
1Biomodelling, 2Medical and Science, NovoSeven Key Projects, 3Biostatistics, Novo Nordisk, Bagsværd, Denmark
Objectives: NN1731 is a recombinant analogue of activated human coagulation factor FVII (FVIIa). Preclinical studies have indicated increased activity of NN1731 compared to native FVIIa in thrombin generation; a key step in the pathway to blood coagulation [1]. Thrombin generation from prothrombin may be measured by the appearance in the blood of prothrombin fragments 1 & 2 (F1+2). A first human dose (FHD) trial investigated the safety and the PK of NN1731, including measurements of F1+2 in plasma. It was attempted to investigate the feasibility of establishing a population PK/PD model of NN1731 pharmacologic effect to enable a future estimation of a relative potency of NN1731 compared to native recombinant FVIIa (rFVIIa, NovoSeven®).
Methods: The FHD trial was a dose escalation trial with 4 cohorts of patients (5, 10, 20 and 30 mcg NN1731/kg). The population PK/PD analysis was performed using NONMEM based on plasma measurements of PK and F1+2 for PD. A linear 2-compartment model of NN1731 PK was developed to describe adequately an initial rapid distribution phase followed by a less rapid elimination phase. An indirect response model was used to describe the formation of F1+2 induced by NN1731.
Results: The population PK/PD model was able to describe well the NN1731 PK and the appearance of F1+2.
Conclusions: Population PK/PD modelling may be used to provide an estimate of the relative potency of NN1731 compared to NovoSeven® once comparable measurements in subjects exposed to NovoSeven® become available.
Reference:
[1] E. Persson et al, PNAS, 96;13583,2001.
