32
4.2 Pharmacokinetic Properties of Berinert
®
As shown in Table 8, Berinert
®
has a short median time to
maximum plasma concentration (T
max
) and a long half-life
(t-½) that is consistent with the rapid onset of clinical efficacy
in patients suffering from HAE attacks.
74
The pharmacokinetics (PK) of Berinert
®
were evaluated in a
prospective, open-label, uncontrolled, single-center study in
40 patients (15 adults with severe HAE, and 19 adults and
6 children with mild HAE).
74
All patients received a single
intravenous injection of Berinert
®
ranging from 500 IU to
1,500 IU. Blood was sampled to determine C1-INH activity
at baseline and for up to 72 hours after the infusion. In
addition, the
in vivo
recovery (IVR) was calculated for the
first 4 hours after the infusion.
Median peak plasma C1-INH activity following administration
of Berinert
®
was reached within 0.5 to 1.0 hours (Table 8),
with no appreciable differences between the groups of
patients. The median volume of distribution of Berinert
®
was between 0.38 (for adults with severe attacks) and
0.57 dL/kg body weight (for adults with mild attack), the
median systemic clearance ranged from 0.9 (for adults with
mild attacks) to 1.1 mL/(kg.h) (for children). The t-½ and the
mean residence time were shortest for adults with severe
attacks, and somewhat shorter for children than for adults
with mild attacks (Table 8).
PK Variable
PK of Berinert
®
74
Population PK of Berinert
®
75
PK PASSION study
76
Median (Range)
a
Estimate of Expected
Mean (90% CI)
b
(n=97)
Mean±SD
(n=23)
Adults With Severe
HAE (
n=15)
Adults With Mild
HAE (
n=19)
Children
(n=6)
T
max
, h
0.5 (0.3–8.0)
1.0 (0.3–32.0)
0.6 (0.1–2.0)
NA
0.5 (0–8)
t-1/2, h
30.9 (10.3–96.0)
39.1 (19.4–90.4)
32.9 (7.3–70.5)
32.7 (16.6–48.8)
62.0±65.6
Mean residence time, h
44.6 (14.9–138.5)
56.5 (28.0–130.5)
47.5 (10.5–101.7)
NA
53.4 (38.25)
Volume of distribution, dL/kg
0.38 (0.24–0.66)
0.57 (0.23–0.69)
0.50 (0.42–0.62)
0.43 (0.40–0.47)
36.8 (13.74)
c
Systemic clearance, mL/(kg·h)
1.0 (0.2–2.4)
0.9 (0.2–1.6)
1.1 (0.5–5.2)
0.92 (0.50–1.33)
0.6±0.4
d
n=Number of patients; CI=Confidence interval; NA=Data not available; t-1/2=half life; T
max
=Time to maximum plasma concentration.
a
Median dose: 1,058 IU (range: 526 to 1,617 IU) or 14.5 IU/kg body weight (range: 9.9 to 22.1 IU/kg).
b
Patients were treated with either 10 or 20 IU/kg body weight.
c
Volume of distribution at the terminal phase in U/%.
d
Clearance measured in IU/h/%.
Table 8 – Pharmacokinetics of Berinert
® 74,75,76
The estimated mean values were 32.7 hours for t-½,
0.43 dL/kg for volume of distribution, and 0.92 mL/(kg.h)
for clearance (Table 8).
The median IVR was highest for adults with severe
attacks (101.4%), and somewhat higher in children
(98.2%) than in adults with mild attacks (74.8%). A
retrospective population PK analysis, based on data from
97 adult patients treated with either 10 or 20 IU/kg
body weight Berinert
®
, confirmed the results previously
observed.
75
Blood was sampled to determine plasma
C1-INH concentrations 0, 1, and 4 hours after each treat-
ment. Sampling extended up to 24 hours after infusion.
Another study (PASSION study) evaluated the PK of intra-
venous vs subcutaneous treatment with 1,000 IU Berinert
®
for 23 patients with HAE, revealing an even higher mean
t-½ of 62 hours, and a mean clearance of 0.6 IU/(h.%) for
intravenous injection.
76
The long t-½ compared with other treatment options pro-
vides an extended period of C1-INH activity even after the
symptoms have subsided.
