n in plasma after single dose
t½ : terminal half-life
MRTIV: mean residence time after an IV administration
Vss: apparent volume distribution at steady-state
CL: clearance
The PK parameters of KOVALTRY for 8 subjects in age group 0 to <6 years and 10 subjects in age group 6 to <12 years are shown in TABLE 5. In general, children <12 years of age demonstrated lower plasma concentrations when compared to PTP children ≥12 years of age.
Table 5: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), Chromogenic Substrate Assay
Parameter [unit]
0 to <6 yrs (N=8)
6 to <12 yrs
(N=10)b
12 to 17 yrs
(N=5)
≥18 yrs
(N=21)
AUC [IU*h/dL]
1544.7 ± 387.1a
1214.5 ± 395.1
1572.0 ± 448.0
2103.4 ± 702.8
Cmax [IU/dL]
89.6 ± 27.4
81.6± 17.8
132.5 ± 46.3
133.1 ± 20.4
t½ [h]
12.1 ± 2.7a
12.0 ± 2.1
14.4 ± 5.5
14.2 ± 3.5
MRTIV [h]
17.7 ± 3.6a
17.8 ± 2.9
19.8 ± 5.8
19.9 ± 4.9
Vss [dL/kg]
0.57 ± 0.13a
0.79 ± 0.23
0.71 ± 0.39
0.50 ± 0.11
CL [dL/h/kg]
0.033 ± 0.009a
0.045 ± 0.016
0.034 ± 0.010
0.027 ± 0.010
a n=7
b One subject considered PK outlier was excluded
Incremental Recovery analysis after 6 months of prophylactic treatment yielded comparable results with incremental recovery after the first dose (see TABLE 6).
Table 6: Incremental Recovery in PTPs
0 to <6 yrs
N=25
6 to 12 yrs
N=25
≥12 yrs
N=115
Chromogenic substrate assay resultsa
Median (Q1; Q3)
(IU/dL per IU/kg)
1.6 (1.3; 1.9)
1.7 (1.4; 2.0)
2.3 (1.8; 2.6)
One-stage assay resultsa
Median (Q1; Q3)
(IU/dL per IU/kg)
-
-
2.2 (1.8; 2.4)
aStart of study
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to eva luate the carcinogenic potential of KOVALTRY or other studies to determine the effects of KOVALTRY on fertility have not been performed. KOVALTRY was negative in the modified in-vitro (Mammalian Mutation and Chromosome Aberration Assay with Mouse Lymphoma Cells) genotoxicity test. KOVALTRY is expected to have no mutagenic potential.
14 CLINICAL STUDIES
The safety and efficacy of KOVALTRY for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis in subjects with severe hemophilia A (<1% Factor VIII) was eva luated in three international (including U.S.) clinical studies. Immunocompetent subjects with severe hemophilia A (Factor VIII activity ≤1%) and no history of Factor VIII inhibitors were eligible for the trials.
Study 1: a multi-center, open-label, cross-over, uncontrolled, study in adolescent and adult (age ≥12 years to <65 years) PTPs (≥150 EDs) eva luated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see TABLE 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 50 IU/kg two or three times per week in which the dosing frequency was assigned by the investigator based on the subject’s individual requirements.
