VONCENTO Powder and solvent for solution for injection/infusion Ref.[108425] Active ingredients: Coagulation factor VIII Von Willebrand factor

von Willebrand disease

The pharmacokinetics of Voncento have been evaluated in VWD patients in the non-bleeding state.

Based on a pharmacokinetic study with 12 subjects ≥12 years with VWD, the following pharmacokinetic characteristics for VWF:RCo, VWF:Ag, VWF:CB and FVIII:C were observed:

AUC = area under the curve; C_max = maximum plasma concentration; C_min = minimum plasma concentration; IU = International Unit; MRT = mean residence time; N = number of subjects; t_max = time to maximum concentration; V_ss = volume of distribution at steady state; VWF:Ag = von Willebrand factor: Antigen; VWF:CB = von Willebrand factor: Collagen Binding; VWF:RCo = von Willebrand factor: Ristocetin Cofactor, FVIII:C = Factor VIII: Coagulant

The relative content of HMW (high molecular weight) VWF multimers in Voncento is on average 86% when compared to normal human plasma (NHP).

Haemophilia A

The pharmacokinetics of Voncento have been evaluated in haemophilia A patients in the non-bleeding state.

Based on a pharmacokinetic study with 16 subjects ≥12 years of age with haemophilia A, the following pharmacokinetic characteristics for FVIII:C were observed:

AUC = area under the curve; C_max = maximum plasma concentration; C_min = minimum plasma concentration; IU = International Unit; MRT = mean residence time; N = number of subjects; tmax = time to maximum concentration; V_ss =
volume of distribution at steady state; FVIII:C = Factor VIII: Coagulant

Paediatric population

von Willebrand disease

The pharmacokinetic data in patients with von Willebrand disease are very similar to those observed in the adult population.

PK of single dose of 80 IU VWF:RCo/kg body weight was evaluated in paediatric subjects less than 12 years of age with severe VWD (see Table below). Following infusion, peak concentrations of VWF markers (VWF:RCo, VWF:Ag, and VWF:CB) and FVIII:C were achieved immediately with a median IR of 0.012-0.016 (IU/mL)/(IU/kg) for VWF markers and 0.018-0.020 (IU/mL)/(IU/kg) for FVIII:C. The median elimination t_1/2 of VWF markers was between 10.00 and 13.48 h whereas FVIII:C had a longer t_1/2 between 11.40 and 19.54 h due to a plateau effect that may represent the net effect of decreasing levels of exogenous FVIII, combined with increasing endogenous FVIII levels. PK parameters from the repeat PK evaluation were similar to those from initial PK. Voncento exposure and disposition were comparable between <6-year-old and 6-12-year-old subjects.

Baseline-adjusted initial PK parameters of VWF and FVIII:C in subjects <6 (N=9) and 6-12 years old (N=5):

AUC = area under the curve; C_max = maximum plasma concentration; IU = International Unit; MRT = mean residence time; N = number of subjects; t_max = time to maximum concentration occurs; V_ss = volume of distribution at steady state; VWF:Ag = von Willebrand factor: Antigen; VWF:CB = von Willebrand factor: Collagen Binding; VWF:RCo = von Willebrand factor: Ristocetin Cofactor, FVIII:C = Factor VIII: Coagulant

Haemophilia A

PK of single dose of 50 IU FVIII/kg body weight was evaluated in 31 paediatric subjects less than 12 years of age with Haemophilia A (see Table below). Following infusion, peak concentrations of FVIII:C were achieved immediately with a median IR of approximately 0.016 (IU/mL)/(IU/kg) for FVIII:C. The median elimination t_1/2 of FVIII:C was approximately 10 h. PK parameters from the repeat PK evaluation were similar to those from initial PK. Voncento exposure and disposition were comparable between <6-year-old and 6-12-year-old subjects.

Baseline-adjusted initial PK parameters of FVIII:C in subjects <6 (N=15) and 6-12 years old (N=16):

AUC = area under the curve; C_max = maximum plasma concentration; C_min = minimum plasma concentration; IU = International Unit; MRT = mean residence time; N = number of subjects; t_max = time to maximum concentration; V_ss = volume of distribution at steady state; FVIII:C = Factor VIII: Coagulant

Voncento contains FVIII and VWF as active ingredients which are derived from human plasma and act like endogenous constituents of plasma. Preclinical studies with repeated dose applications (chronic toxicity, carcinogenicity and mutagenicity) cannot be reasonably performed in conventional animal models due to the development of antibodies following the application of heterologous human proteins.