NovoSeven Mechanism of Action

Pharmacotherapeutic group: Blood coagulation factors. ATC code: B02BD08.
Pharmacology: Pharmacodynamics: Mechanism of action: NovoSeven contains activated recombinant coagulation factor VII. The mechanism of action includes the binding of factor VIIa to exposed tissue factor. This complex activates factor IX into factor IXa and factor X into factor Xa, leading to the initial conversion of small amounts of prothrombin into thrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury and to the formation of the haemostatic plug by converting fibrinogen into fibrin. Pharmacological doses of NovoSeven activate factor X directly on the surface of activated platelets, localised to the site of injury, independently of tissue factor. This results in the conversion of prothrombin into large amounts of thrombin independently of tissue factor.
Pharmacodynamic effects: The pharmacodynamic effect of factor VIIa gives rise to an increased local formation of factor Xa, thrombin and fibrin.
The time to peak coagulant activity after administration of NovoSeven was approximately 10 minutes in healthy subjects and patients with haemophilia.
A theoretical risk for the development of systemic activation of the coagulation system in patients suffering from underlying diseases predisposing them to DIC cannot be totally excluded.
Clinical efficacy and safety: Congenital FVII deficiency: In an observational registry (F7HAEM-3578) covering subjects with congenital FVII deficiency, 3 out of 91 surgical patients experienced thromboembolic events.
Severe postpartum haemorrhage: The efficacy and safety of NovoSeven was assessed in 84 women with severe postpartum haemorrhage in a multicentre, open-label clinical trial. Patients were randomised either to treatment with a single dose of 60 μg/kg of NovoSeven (in addition to standard of care; N=42) or to reference therapy (standard of care alone; N=42), following failure of uterotonics (sulprostone). The treatment groups were well balanced in terms of demographic characteristics and postpartum haemorrhage treatment prior to randomisation. Fibrinogen and tranexamic acid were part of standard of care.
Information on fibrinogen/tranexamic acid use was available from approximately 57% of patients in the NovoSeven group and 43% of patients in the reference group. Of these, about 40% of the patients in both groups received fibrinogen and/or tranexamic acid. Bleeding was considered to have stopped (i.e. treatment success) if the estimated blood flow decreased to less than 50 ml per 10 minutes within the 30 minutes following randomisation. If the bleeding was uncontrolled or intractable, invasive procedures were considered.
In the primary analysis, fewer women in the NovoSeven group (21 vs 35) had at least one embolisation and/or ligation procedure compared to the reference group, corresponding to a statistically significant 40% relative reduction in risk for the NovoSeven group compared to the reference group (relative risk = 0.60 (95% confidence interval: 0.43 - 0.84, p=0.0012)).
In the reference group, 8 of the 42 patients received late NovoSeven as a compassionate treatment in an attempt to avoid salvage hysterectomy, which succeeded in 2 cases.
Pharmacokinetics: Healthy subjects: Distribution, elimination and linearity: Using the FVII clotting assay, the pharmacokinetics of rFVIIa were investigated in 35 healthy Caucasian and Japanese subjects in a dose-escalation study. Subjects were stratified according to sex and ethnic group and dosed with 40, 80 and 160 μg rFVIIa per kg body weight (3 doses each) and/or placebo. The pharmacokinetics were similar across sex and ethnic groups. The mean steady state volume of distribution ranged from 130 to 165 ml/kg, the mean values of clearance ranged from 33.3 to 37.2 ml/h×kg.
The mean terminal half-life ranged from 3.9 to 6.0 hours.
The pharmacokinetic profiles indicated dose proportionality.
Haemophilia A and B with inhibitors: Distribution, elimination and linearity: Using the FVIIa assay, the pharmacokinetic properties of rFVIIa were studied in 12 paediatric (2-12 years) and 5 adult patients in non-bleeding state.
Mean volume of distribution at steady state was 196 ml/kg in paediatric patients versus 159 ml/kg in adults.
The mean clearance was approximately 50% higher in paediatric patients relative to adults (78 versus 53 ml/h×kg), whereas the mean terminal half-life was determined to 2.3 hours in both groups.
Clearance appears related with age, therefore in younger patients clearance may be increased by more than 50%.
Dose proportionality was established in children for the investigated doses of 90 and 180 μg per kg body weight, which is in accordance with previous findings at lower doses (17.5 - 70 μg/kg rFVIIa).
Factor VII deficiency: Distribution and elimination: Single dose pharmacokinetics of rFVIIa, 15 and 30 μg per kg body weight, showed no significant difference between the two doses used with regard to dose-independent parameters: Volume of distribution at steady state (280-290 ml/kg), half-life (2.82-3.11 h), total body clearance (70.8-79.1 ml/h×kg) and mean residence time (3.75-3.80 h). The mean in vivo plasma recovery was approximately 20%.
Glanzmann's thrombasthenia: The pharmacokinetics of NovoSeven in patients with Glanzmann's thrombasthenia have not been investigated, but are expected to be similar to the pharmacokinetics in haemophilia A and B patients.
Severe postpartum haemorrhage: Pharmacokinetics of NovoSeven in patients with severe postpartum haemorrhage have not been investigated.
Toxicology: Preclinical safety data: All findings in the preclinical safety programme were related to the pharmacological effect of rFVIIa.
A potential synergistic effect of combined treatment with rFXIII and rFVIIa in an advanced cardiovascular model in cynomolgus monkey resulted in exaggerated pharmacology (thrombosis and death) at a lower dose level than when administering the individual compounds.