A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Antagon Pharmacology, Pharmacokinetics, Studies, Metabolism - Ganirelix
Antagon Pharmacology, Pharmacokinetics, Studies, Metabolism - Ganirelix
CLINICAL PHARMACOLOGY
The pulsatile release of GnRH stimulates the synthesis and secretion of luteinizing
hormone (LH) and follicle-stimulating hormone (FSH). The frequency of LH pulses
in the mid and late follicular phase is approximately 1 pulse per hour. These
pulses can be detected as transient rises in serum LH. At midcycle, a large
increase in GnRH release results in an LH surge. The midcycle LH surge initiates
several physiologic actions including: ovulation, resumption of meiosis in the
oocyte, and luteinization. Luteinization results in a rise in serum progesterone
with an accompanying decrease in estradiol levels.
Antagon™ (ganirelix acetate) Injection acts by competitively blocking the GnRH
receptors on the pituitary gonadotroph and subsequent transduction pathway.
It induces a rapid, reversible suppression of gonadotropin secretion. The suppression
of pituitary LH secretion by Antagon™ is more pronounced than that of FSH. An
initial release of endogenous gonadotropins has not been detected with Antagon™,
which is consistent with an antagonist effect. Upon discontinuation of Antagon™,
pituitary LH and FSH levels are fully recovered within 48 hours.
Pharmacokinetics
The pharmacokinetic parameters of single and multiple injections of Antagon™
(ganirelix acetate) Injection in healthy adult females are summarized in Table
I. Steady state serum concentrations are reached after 3 days of treatment.
The pharmacokinetics of ganirelix acetate are dose-proportional in the dose
range of 125 to 500 µg.
TABLE I: Mean (SD) pharmacokinetic parameters
of 250 µg of Antagon™ following a single subcutaneous (SC) injection (n=15)
and daily SC injections (n=15) for seven days.
|
|
t max
h |
t ˝
h |
C max
ng/mL |
AUC
ng·h/mL |
CL / F
L/h |
V d /F
L |
|
Antagon™ single dose
|
1.1 (0.3) |
12.8 (4.3) |
14.8 (3.2) |
96 (12) |
2.4 (0.2) ** |
43.7 (11.4) ** |
|
Antagon™ multiple dose
|
1.1 (0.2) |
16.2 (1.6) |
11.2 (2.4) |
77.1 (9.8) |
3.3 (0.4) |
76.5 (10.3) |
|
t max Time to maximum concentration
t ˝ Elimination half-life
C max Maximum serum concentration
AUC Area under the curve; Single dose: AUC 0-(infinity)
; multiple dose: AUC 0-24
V d Volume of distribution
** Based on intravenous administration
CL Clearance = Dose/AUC 0-(infinity)
F Absolute bioavailability
|
Absorption
Ganirelix acetate is rapidly absorbed following subcutaneous injection with
maximum serum concentrations reached approximately one hour after dosing. The
mean absolute bioavailability of Antagon™ following a single 250 µg subcutaneous
injection to healthy female volunteers is 91.1%.
Distribution
The mean (SD) volume of distribution of Antagon™ in healthy females following
intravenous administration of a single 250 µg dose is 43.7 (11.4) liters (L).
In vitro protein binding to human plasma is 81.9%.
Metabolism
Following single dose intravenous administration of radiolabeled Antagon™ to
healthy female volunteers, Antagon™ is the major compound present in the plasma
(50-70% of total radioactivity in the plasma) up to 4 hours and urine (17.1-18.4%
of administered dose) up to 24 hours. Antagon™ is not found in the feces. The
1-4 peptide and 1-6 peptide of Antagon™ are the primary metabolites observed
in the feces.
Excretion
On average, 97.2% of the total radiolabeled Antagon™ dose is recovered in the
feces and urine (75.1% and 22.1%, respectively) over 288 h following intravenous
single dose administration of 1 mg [ 14 C]-ganirelix acetate. Urinary
excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau
192 h after dosing.
Special Populations
The pharmacokinetics of ganirelix acetate have not been determined in special
populations such as geriatric, pediatric, renally impaired and hepatically impaired
patients (see PRECAUTIONS ).
Drug-Drug Interactions
Formal in vivo or in vitro drug-drug interaction studies have
not been conducted (see PRECAUTIONS ). Since Antagon™ can suppress the secretion
of pituitary gonadotropins, dose adjustments of exogenous gonadotropins may
be necessary when used during controlled ovarian hyperstimulation (COH).
Clinical Studies
The efficacy of Antagon™ (ganirelix acetate) Injection was established in two
adequate and well-controlled clinical studies which included women with normal
endocrine and pelvic ultra-sound parameters. The studies intended to exclude
subjects with polycystic ovary syndrome (PCOS) and subjects with low or no ovarian
reserve. One cycle of study medication was administered to each randomized subject.
For both studies, the administration of exogenous recombinant FSH [Follistim®
(follitropin beta for injection)] 150 IU daily was initiated on the morning
of Day 2 or 3 of a natural menstrual cycle. Antagon™ was administered on the
morning of Day 7 or 8 (Day 6 of recombinant FSH administration). The dose of
recombinant FSH administered was adjusted according to individual responses
starting on the day of initiation of Antagon™. Both recombinant FSH and Antagon™
were continued daily until at least three follicles were 17 mm or greater in
diameter at which time hCG [Pregnyl® (chorionic gonadotropin for injection,
USP)] was administered. Following hCG administration, Antagon™ and recombinant
FSH administration were discontinued. Oocyte retrieval, followed by in vitro
fertilization (IVF) or intracytoplasmatic sperm injection (ICSI), was subsequently
performed.
In a multicenter, double-blind, randomized, dose-finding study, the safety
and efficacy of Antagon™ were evaluated for the prevention of LH surges in women
undergoing COH with recombinant FSH. Antagon™ doses ranging from 62.5 µg to
2000 µg and recombinant FSH were administered to 332 patients undergoing COH
for IVF (see TABLE II). Median serum LH on the day of hCG administration decreased
with increasing doses of Antagon™. Median serum E 2 (17(beta)-estradiol)
on the day of hCG administration was 1475, 1110, and 1160 pg/mL for the 62.5,
125, and 250 µg doses, respectively. Lower peak serum E 2 levels
of 823, 703, and 441 pg/mL were seen at higher doses of Antagon™ 500, 1000,
and 2000 µg, respectively. The highest pregnancy and implantation rates were
achieved with the 250 µg dose of Antagon™ as summarized in Table II.
TABLE II: Results from the multicenter, double-blind,
randomized, dose-finding study to assess the efficacy of Antagon™ to prevent
premature LH surges in women undergoing COH with recombinant FSH.
|
|
Daily dose (µg) of Antagon™ |
|
|
62.5 µg |
125 µg |
250 µg |
500 µg |
1000 µg |
2000 µg |
|
No. subjects receiving
Antagon™
|
31 |
66 |
70 |
69 |
66 |
30 |
|
No. subjects with ET ***
|
27 |
61 |
62 |
54 |
61 |
27 |
|
No. of subjects with
LH rise ≥ 10 mIU/mL *
|
4 |
6 |
1 |
0 |
0 |
0 |
|
Serum LH (mIU/mL)
on day of hCG **
|
3.6 |
2.5 |
1.7 |
1.0 |
0.6 |
0.3 |
|
5 th -95 th percentiles
|
0.6-19.9 |
0.6-11.4 |
<0.25-6.4 |
0.4-4.7 |
<0.25-2.2 |
<0.25-0.8 |
|
Serum E 2 (pg/mL)
on day of hCG **
|
1475 |
1110 |
1160 |
823 |
703 |
441 |
|
5 th -95 th percentiles
|
645-3720 |
424-3780 |
384-3910 |
279-2720 |
284-2360 |
166-1940 |
|
Vital pregnancy rate ^
|
|
|
|
|
|
|
|
per attempt, n (%)
|
7 (22.6) |
17 (25.8) |
25 (35.7) |
8 (11.6) |
9 (13.6) |
2 (6.7) |
|
per transfer, n (%)
|
7 (25.9) |
17 (27.9) |
25 (40.3) |
8 (14.8) |
9 (14.8) |
2 (7.4) |
|
Implantation rate (%) r
|
14.2 (26.8) |
16.3 (30.5) |
21.9 (30.6) |
9.0 (23.7) |
8.5 (21.7) |
4.9 (20.1) |
|
(Protocol 38602)
|
| * Following initiation of Antagon™ therapy. Includes subjects
who have complied with daily injections
** Median values
r Mean (standard deviation)
*** ET: Embryo Transfer
^ As evidenced by ultrasound at 5-6 weeks following
ET
|
Transient LH rises alone were not deleterious to achieving pregnancy with Antagon™
at doses of 125 µg (3/6 subjects) and 250 µg (1/1 subjects). In addition, none
of the subjects with LH rises ≥ 10 mIU/mL had premature luteinization indicated
by a serum progesterone above 2 ng/mL.
A multicenter, open-label, randomized study was conducted to assess the efficacy
and safety of Antagon™ in women undergoing COH. Follicular phase treatment with
Antagon™ 250 µg was studied using a luteal phase GnRH agonist as a reference
treatment. A total of 463 subjects were treated with Antagon™ by subcutaneous
injection once daily starting on Day 6 of recombinant FSH treatment. Recombinant
FSH was maintained at 150 IU for the first 5 days of ovarian stimulation and
was then adjusted by the investigator on the sixth day of gonadotropin use according
to individual responses. The results for the Antagon™ arm are summarized in
Table III.
TABLE III: Results from the multicenter, open-label,
randomized study to assess the efficacy and safety of Antagon™ in women
undergoing COH.
| |
Antagon™ 250 µg
|
|
No. subjects treated
|
463
|
|
Duration of GnRH analog (days) § y
|
5.4 (2.0)
|
|
Duration of recombinant FSH (days) § y
|
9.6 (2.0)
|
|
Serum E 2 (pg/mL) on day of hCG **
|
1190
|
|
5 th -95 th percentiles
|
373-3105
|
|
Serum LH (mlU/mL) on day of hCG **
|
1.6
|
|
5 th -95 th percentiles
|
0.6-6.9
|
|
No. of subjects with LH rise ≥ 10 mlU/mL *
|
13
|
|
No. of follicles > 11 mm § y
|
10.7 (5.3)
|
|
No. of subjects with oocyte retrieval
|
440
|
|
No. of oocytes y
|
8.7 (5.6)
|
|
Fertilization rate
|
62.1%
|
|
No. subjects with ET ***
|
399
|
|
No. of embryos transferred y
|
2.2 (0.6)
|
|
No. of embryos y
|
6.0 (4.5)
|
|
Ongoing pregnancy rates ^ §
|
|
|
per attempt, n (%) ""
|
94 (20.3)
|
|
per transfer, n (%)
|
93 (23.3)
|
|
Implantation rate (%) y
|
15.7 (29)
|
|
(Protocol 38607)
|
| * Following initiation of Antagon™ therapy
** Median values
§ Restricted to subjects with hCG injection
y Mean (standard deviation)
*** ET: Embryo Transfer
^ As evidenced by ultrasound at 12-16 weeks
following ET
"" Includes one patient who achieved pregnancy
with intrauterine induction.
Some centers were limited to the transfer of ≤ 2 embryos based
on local practice standards
|
The mean number of days of Antagon™ treatment was 5.4 (2-14). There was no
incidence of drug related allergic reactions within the adequate and well-controlled
clinical studies.
LH Surges
The midcycle LH surge initiates several physiologic actions including: ovulation,
resumption of meiosis in the oocyte, and luteinization. In 463 subjects administered
Antagon™ 250 µg, a premature LH surge prior to hCG administration, (LH rise
≥ 10 mIU/mL with a significant rise in serum progesterone > 2 ng/mL,
or a significant decline in serum estradiol) occurred in less than 1% of subjects.
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