8) 117.7 (14) 130.4 (26)
t1/2 (hours) 14.7 (27) 13.8 (32) 17.4 (39) 21.7 (33)
AUCinf (IU*hour/dL) 2305 (42) 2197 (38) 3063 (40) 4110 (38)
CL (mL/hour/kg) 2.4 (42) 2.7 (42) 1.6 (39) 1.2 (34)
Vss (mL/kg) 44.2 (25) 47.3 (28) 36.4 (12) 37.3 (26)
MRT (hours) 18.1 (27) 17.8 (35) 23.4 (43) 27.4 (28)b
PK parameters are presented in geometric mean.
Abbreviations: IR = Incremental recovery; t1/2 = terminal half-life; AUC = area under the FVIII activity time profile; CL = clearance; Vss = volume of
distribution at steady-state; MRT = mean residence time; CV% = coefficient of variation a IR and FVIII recovery were assessed 30 minutes post-dosing 50 IU/kg for patients ≥12 years and 60 minutes post-dosing 50 IU/kg (first sample) for
children <12 years. b Calculation based on 64 profiles.
In the single-dose PK assessment in adult subjects, whose body mass index (BMI) ranged from 17-35 kg/m2
, differences
were noted for individuals who were overweight (BMI 25 - <30 kg/m2
) and obese (BMI 30 - <35 kg/m2
). Incremental
recovery was increased by approximately 17% and 41%, AUC was increased by approximately 10% and 27%, and clearance
was decreased by approximately 8% and 23% respectively, all in comparison to those subjects with BMI <25 kg/m2
. There is
insufficient data to recommend specific dose adjustments for overweight and obese patients. The dose may be adjusted asnecessary per prescriber’s discretion.
Observed pre-dose (trough) and post-dose (peak) plasma Factor VIII activity levels at steady-state during prophylactictreatment with ESPEROCT are presented in Table 4 by dose regimen and age range.
Table 4:Steady-state trough and peak plasma FVIII activity by age and dose regimen, chromogenic assay (geometric
mean [95% CI])
Dose
Regimen
60 IU/kg twice weekly**
(50–75 IU/kg)
50 IU/kg Q4D* 75 IU/kg Q7D*
Age range
No. patients
<6 years
N=31
6–<12 years
N=34
12–<18 years
N=23
≥18 years
N=143
12–<18 years
N=6
≥18 years
N=29
Trough,
IU/dL
1.2
(0.8; 1.6)
2.0
(1.5; 2.7)
2.7
(1.8; 4.0)
3.0
(2.6; 3.5)
0.6
(0.2; 1.6)
1.3
(0.9; 2.0)
Peak,
IU/dL
125.0
(118.7; 131.6)
143.3
(136.8; 150.2)
125.1
(116.0; 135.0)
137.9
(133.9; 142.2)
198.0
(166.8; 235.2)
197.9
(184.9; 212.7)
*Data included in analysis: adolescents/adults Main Phase until Visit 8 (end of the Main Phase) 50 IU/kg Q4D, and extension 1 for 75IU/kg Q7D. Only measurements collected at steady-state for the given prophylaxis treatment are included in the analyses.
**Data included in analysis: pediatric Main Phase 60 IU/kg (50–75 IU/kg) twice weekly. Only measurements collected at steady-state for
the given prophylaxis treatment are included in the analyses.
Time of Factor VIII Activity Above 5%
Steady-state Factor VIII activity profiles were estimated using a one-compartment model with first-order elimination with PK
parameters of clearance (CL) and volume of distribution (Table 5). Pharmacokinetic predictions showed that in all age
groups, patients dosed twice weekly (dosing interval alternating between 3 and 4 days) or Q4D will be above 5% Factor VIII
activity (i.e., in the range of mild hemophilia) for the majority of time (72–95% of time). Patients dosed with 50 IU/kg every
4 days will be above 1% Factor VIII activity 100% of the dosing interval. Patients dosed with 75 IU/kg every 7 days are
predicted to be above 5% |
