Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Bio Products Laboratory Limited, Dagger Lane, Elstree, Hertfordshire, WD6 3BX, United Kingdom
Pharmacotherapeutic Group: antihaemorrhagics, blood coagulation factor VIII
ATC code: B02BD02
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.
In addition to its role as a factor VIII protecting protein, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.
In a multicentre, non-randomised, open-label study in 55 subjects aged >12 years with severe haemophilia A (≤1% activity) and previously treated with Factor VIII, Optivate was administered for approximately 2 years either as routine prophylaxis or on-demand therapy to treat a bleed. Patients using Optivate prophylactically (n=5) experienced fewer bleeds (27 on average) than those only using it on demand (n=50; 65 bleeds on average). The mean dose per bleed per subject was 60 and 27 IU/kg, respectively.
In a multicentre, non-randomised, open-label study in 25 subjects aged 1 to 6 years with severe haemophilia A (≤1% activity), Optivate was administered for 6 months either as routine prophylaxis or on-demand therapy to treat a bleed. All but one had been treated with Factor VIII prior to study entry. Children using Optivate prophylactically (n=5) experienced fewer bleeds (8 on average) than those only using it on demand (n=20; 13 bleeds on average). The mean dose per month was 299 IU/kg for patients receiving Optivate prophylactically compared to 150 IU/kg for patients receiving Optivate on demand. The mean dose per bleed per subject was 36 and 42 IU/kg, respectively. Three subjects reported 5 adverse drug reactions, all of which were mild in intensity: infusion site reactions (4) and rash (1 report).
The pharmacokinetics of Optivate have been evaluated in 15 patients (≥12 years old) with severe haemophilia A (<2% activity) after bolus doses of 50 IU/kg. The results are presented in the table below.
| Parameter | Mean | 95% CI |
|---|---|---|
| Non-compartmental terminal half-life (hours) | 12.4 | 10.94-13.83 |
| Mean residence time (hours) | 17.5 | 15.99-18.92 |
| Clearance (ml/hour/kg) | 3.1 | 2.71-3.51 |
| Area under curve (AUC0-48h) (IU.h/ml) | 16.1 | 13.97-18.28 |
| Area under curve (AUC0-inf) (IU.h/ml) | 17.31 | 14.98-19.65 |
| Volume of distribution (ml/kg) | 53.4 | 46.2-60.52 |
| Initial (Alpha) half-life (hours) | 2.2 | 1.48-2.88 |
| Elimination (Beta) half-life (hours) | 12.6 | 11.33-13.92 |
| Incremental recovery (IU/dl per IU/kg) | 2.5 | 2.22-2.74 |
CI = Confidence Interval
During the clinical trials, there were 309 assessments of incremental recovery, all based on the maximum FVIII:C in the first hour. These assessments have involved 27 batches of Optivate and 70 adults with severe haemophilia A. The overall values of incremental recovery were as follows:
| Mean | 2.7 IU/dl per IU/kg |
| 95% CI | 2.53-2.80 IU/dl per IU/kg |
| Median | 2.6 IU/dl per IU/kg |
Pharmacokinetic data are not available in children younger than 12 years old.
The factor VIII and von Willebrand factor in Optivate are normal constituents of human plasma and act in the same way as the endogenous proteins, therefore, safety testing is not relevant.
However, an acute toxicity study and a repeated dose toxicity study in mice indicated that the Optivate formulation was not toxic, even at levels up to 20 times that likely to be used in man. In these studies, the various constituents of the product were administered to the test animals in different, greater, amounts for each excipient, compared to that in a clinical dose.
It is scientifically inappropriate to conduct genotoxicity or carcinogenicity studies with plasma coagulation factor VIII with or without its natural stabiliser, von Willebrand factor.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
