Source: Medicines Authority (MT) Revision Year: 2020 Publisher: Kedrion S.p.A. Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca)
Pharmacotherapeutic Group: antihemorrhagics, 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 results 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, annualized 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.
10 severe Hemophilia A patients (median age 15 years, range 5-51) with high inhibitor titre, included in the PROFIT registry managed by the Italian Association of Hemophilia Centres (AICE), have been treated with EMOCLOT for inhibitor eradication using an immunotolerance induction (ITI). 8 patients out of these 10 received first line ITI and 2 underwent rescue ITI, following a previous failed attempt with a different FVIII concentrate. 5 patients were treated with intermediate/high daily dosing regimens (100/200 IU/Kg/die), and 5 were treated on alternate days or 3 times a week at variable doses (50-150 IU/kg). A complete or partial response, persistent after a mean follow up of 9 years, has been obtained in 50% of cases. In the 4 patients who reached a complete success, the mean time to inhibitor eradication was 26 months.
Additionally, the experience on 11 patients (median age 17 years) with high inhibitor titre undergoing ITI with EMOCLOT has been described in literature; overall, ITI was successful in 9/11 patients (82%), with complete inhibitor eradication in 4 (36%) and partial success in 5 (45%).
125 inhibitor-free children below 6 years of age, with no or minimal previous exposure to FVIII, have been treated with plasma derived FVIII within a controlled, randomized study (SIPPET), aimed at assessing the incidence of inhibitors among patients treated with plasma-derived or recombinant factor VIII. 61 patients out of the abovementioned 125 have been treated with EMOCLOT according to an on-demand or prophylaxis regimen. Namely, 34 patients out of 61 received an on-demand treatment, 5 standard prophylaxis (3 infusions/week), 15 modified prophylaxis (2 infusions/week) and 7 different combinations of treatment regimens.
A post-hoc analysis, aimed at evaluating the annualized bleeding rate (ABR) only in patients treated with EMOCLOT, registered an ABR of 4.2 (342 episodes) in patients following an on demand regimen, 7.5 (25 episodes) in patients following standard prophylaxis (for a total of 25 bleeding episodes registered in this group, 24 occurred in 1 patient; excluding this patient from the analysis, ABR decreased to 0.24), 5.8 (92 episodes) in patients following modified prophylaxis and 5.9 (60 episodes) in patients treated with different regimen combinations.
After injection of the product, approximately two thirds to three quarters of factor VIII remain in blood circulation.
The level of factor VIII activity reached in the plasma varies between 80-120% of the predicted plasma factor VIII activity.
Plasma factor VIII activity decreases by two-phase exponential decay.
In the initial phase, distribution between the intravascular compartment and other body fluids occurs with a half-life of elimination from the plasma of 3-6 hours.
In the subsequent slower phase (which probably reflects the consumption of factor VIII) the half-life varies between 8-20 hours, the average being 12 hours. This appears to correspond to the true biological half-life.
Pharmacokinetic properties of EMOCLOT have been evaluated during the clinical study “Evaluation of the pharmacokinetic and clinical efficacy of the concentrate of Factor VIII, EMOCLOT D.I., in patients affected by haemophilia A” (study code KB030), conducted on 15 patients affected by severe haemophilia A (with FVIII level <1). PK parameters have been calculated on two single infusions (at a dosage of 25 IU/kg) performed at a distance of 3-6 months. In the period between the two infusions, patients have been treated with EMOCLOT according to their usual therapeutic regimen (on demand treatment or prophylaxis).
Average values for EMOCLOT PK parameters evaluated during the study are reported in the following table.
| First infusion | Second infusion | |||
|---|---|---|---|---|
| Without subtraction of baseline | With subtraction of baseline | Without subtraction of baseline | With subtraction of baseline | |
| AUC0-t (IU·ml-1·h) | 10.94 | 9.96 | 10.75 | 8.95 |
| AUC0-∞ (IU·ml-1·h) | 13.08 | 11.22 | 12.07 | 9.89 |
| Cltot (ml·h-1·kg-1) | 2.63 | 2.89 | 2.51 | 2.99 |
| Incremental recovery (%) | 2.688 | 2.671 | ||
| t1/2α (h) | 0.543 | 0.768 | ||
| t1/2β (h) | 12.05 | 15.16 | ||
Although there are no specific data for paediatric population, the few published data related to PK studies have not shown major differences between adults and children suffering from the same disorder.
Human plasma coagulation factor VIII (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 impractical due to interference with developing antibodies to heterologous protein.
Even doses over and above the recommended human dosage per kg of body weight show no toxic effects on laboratory animals.
Since clinical experience provides no indication for oncogenic and mutagenic effects of human plasma coagulation factor VIII, experimental studies, particularly in heterologous species, are not considered imperative.
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