hat is traceable to the current World Health Organization (WHO)international standard for FVIII concentrate, and eva luated by appropriate methodologies to ensure the accuracy of theresults. ESPEROCT is available in single-dose vials that contain nominally 500, 1000, 1500, 2000, or 3000 IU of FVIII. Eachvial of ESPEROCT is labeled with the actual FVIII activity. After reconstitution with the supplied diluent (0.9% saline),each mL of the solution contains approximately 125, 250, 375, 500, or 750 IU of FVIII, respectively.
The FVIII protein in ESPEROCT is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology,and contains a truncated B domain, which is O-glycosylated. The polypeptide part of the molecule has a molecular mass of166 kDa (calculated excluding post-translational modifications) and represents a heterodimer of a heavy chain and a lightchain, which are held together by non-covalent interactions. The recombinant FVIII protein is purified using a series ofchromatographic steps, one of which is affinity chromatography, with the use of a monoclonal antibody to selectively isolatethe rFVIII from the cell culture medium. The 40-kDa PEG molecule is conjugated to the O-glycan moiety of the B domainusing an enzymatic reaction to produce a glycopegylated FVIII (FVIII-PEG). The purification process includes two viralclearance steps, namely detergent (Triton X-100) treatment for inactivation of enveloped viruses, and 20-nm filtration forremoval of enveloped and non-enveloped viruses. No additives of human or animal origin are used during the manufacturingprocess and formulation of ESPEROCT.
In the blood circulation, when FVIII-PEG is activated by thrombin, the B-domain portion with the attached PEG moiety iscleaved off, and the resulting activated FVIII (FVIIIa) is similar in structure and function to native FVIIIa.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ESPEROCT, a glycopegylated form of recombinant anti-hemophilic factor, temporarily replaces the missing coagulationFactor VIII needed for effective hemostasis in congenital hemophilia A patients. The Factor VIII in ESPEROCT isconjugated to a 40-kDa polyethylene glycol molecule which increases the half-life and decreases the clearance compared tothe non-pegylated molecule.
12.2 Pharmacodynamics
The administration of ESPEROCT increases plasma levels of Factor VIII and can temporarily correct the coagulation defect inhemophilia A patients, as reflected by a decrease in activated partial thromboplastin time (aPTT).
12.3 Pharmacokinetics
All pharmacokinetic studies with ESPEROCT were conducted in previously treated subjects with severe hemophilia A(Factor VIII<1%). In total, 129 single-dose pharmacokinetic profiles of ESPEROCT were eva luated in 86 subjects (including24 pediatric subjects, 1–<12 years).
Table 3 shows data for subjects who each received a single dose of 50 IU/kg. The plasma samples were analyzed using theone-stage clotting assay. There was a trend of increasing incremental recovery and AUC, and decreasing clearance, with age.
Table 3: Single-dose PK parameters of ESPEROCT 50 IU/kg, by age, using one-stage clotting assay (geometric mean(CV%))
PK Parameter
No. of subjects
1 to <6 years
N=12
6 to <12 years
N=10
12 to <18 years
N=3
>18 years
N=42
No. of profiles 12 10 5 78
IR (IU/dL) per IU/kg)a 1.82 (32) 1.67 (22) 2.45 (16) 2.53 (24)
FVIII recovery (IU/dL)a 103.2 (27) 98.7 (1 |
