ainer closure system consists of a 10 mL, Type I glass vial sealed with a bromobutyl grey stopper and an aluminum crimp seal with plastic flip-off cap plus vial adapter. The vial adapter was designed to connect with the sterile water for injection (sWFI), prefilled diluent syringe. KOVALTRY is formulated with the following excipients: 2.2% glycine, 1% sucrose, 30 mM sodium chloride, 2.5 mM calcium chloride, 20 mM histidine and 80 ppm polysorbate 80. The pH of the reconstituted product is 6.6 to 7.0. Intravenous administration of sucrose contained in KOVALTRY will not affect blood glucose level.
The active substance in KOVALTRY is the unmodified full length recombinant Factor VIII glycoprotein comprising the human derived amino acid sequence. Post-translational modifications are similar to those of endogenous Factor VIII including glycosylation sites and sulfation of tyrosine sites. Manufacturing and quality controls ensure that both galactose-alpha-1,3-galactose (alpha-Gal) and N-glycolyl neuraminic acid (NGNA) content are below the 1% limit of detection established for each analytical method.
KOVALTRY is produced by a genetically engineered Baby Hamster Kidney (BHK) cell line into which the human Factor VIII gene was introduced together with the human heat shock protein 70 (HSP 70) gene. HSP 70 is an intracellular protein that improves proper folding of the Factor VIII protein. While KOVALTRY and Kogenate FS have the same protein backbone, human- and animal-derived raw materials are not added to the cell culture, purification, or formulation processes for KOVALTRY. In the manufacturing process for KOVALTRY, recombinant Factor VIII is secreted into cell culture medium and is purified from process- and product-related impurities using a series of chromatography and filtration steps. The production process incorporates two dedicated viral clearance steps: (1) a detergent treatment step for inactivation and (2) a 20 nanometer filtration step for removal of viruses and potential protein aggregates.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
KOVALTRY temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.
12.2 Pharmacodynamics
Plasma clotting time as measured by the activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Treatment with KOVALTRY normalizes the aPTT.
12.3 Pharmacokinetics
The pharmacokinetics (PK) of KOVALTRY were investigated in PTPs (0 to 61 years of age) with severe Hemophilia A following administration of 50 IU/kg of KOVALTRY. The PK parameters of KOVALTRY are presented in TABLE 4 (one-stage clotting assay) and TABLE 5 (chromogenic substrate assay). The PK of KOVALTRY were similar between single and repeat dosing (in 19 subjects following 6 to 12 months of prophylaxis).
Table 4: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), One-Stage Clotting Assay
Parameter [unit]
12 to 17 yrs (N=5)
≥18 yrs
(N=21)
AUC [IU*h/dL]
1013.9 ± 286.8
1601.3 ± 520.0
Cmax [IU/dL]
91.7 ± 28.7
99.7 ± 14.9
t½ [h]
11.7 ± 1.11
14.3 ± 3.7
MRTIV [h]
16.1 ± 0.8
19.8 ± 5.7
Vss [dL/kg]
0.85 ± 0.24
0.63 ± 0.11
CL [dL/h/kg]
0.053 ± 0.017
0.035 ± 0.012
AUC: area under the curve
Cmax: maximum drug concentratio |
