Coagulation factor VIII

Pharmacodynamic properties

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 patientยดs circulation.

Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X (factor Xa). 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.

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.

Data on successfully performed Immune Tolerance Induction (ITI) have been collected in patients with haemophilia A who have developed inhibitors to factor VIII.

Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.

Pharmacokinetic properties

Plasma factor VIII activity decreases by a two-phase exponential decay after intravenous use. In the initial phase, distribution between intravascular and other compartments (body fluids) occurs with a half-life of elimination from the plasma of 1 to 8 hours. In the subsequent phase the half-life varies between 5-18 hours, with an average of about 12 hours. This appears to correspond to the true biological half-life.

The incremental recovery of coagulation factor VIII is approximately 0.020 ยฑ 0.003 IU/ml/IU/kg b.w. The level of factor VIII activity after intravenous use of 1 IU factor VIII per kg b.w. is about 2%.

Other pharmacokinetic parameters of coagulation factor VIII are:

  • Area under the curve (AUC): about 17 IU x h/ml
  • Mean residence time (MRT): about 15 h
  • Clearance: about 155 ml/h.

Preclinical safety data

Human plasma coagulation factor VIII (from the concentrate) is a normal constituent of the human plasma and acts like the endogenous factor VIII. Single dose toxicity testing is of no relevance since higher doses result in overloading. Repeated dose toxicity testing in animals is impracticable due to the interference with developing antibodies to heterologous protein.

Even doses of several times the recommended human dose per kilogram body weight show no toxic effects on laboratory animals.

Since clinical experience provides no hint for tumorigenic and mutagenic effects of human plasma coagulation factor VIII, experimental studies, particularly in heterologous species, are not considered imperative.

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