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
Gonal-F Pharmacology, Pharmacokinetics, Studies, Metabolism - Follitropin Alfa
Gonal-F Pharmacology, Pharmacokinetics, Studies, Metabolism - Follitropin Alfa
CLINICAL PHARMACOLOGY
Gonal-F® (follitropin alfa for injection) stimulates ovarian
follicular growth in women who do not have primary
ovarian failure. FSH,
the active component of Gonal-F® is the primary
hormone responsible
for follicular recruitment and development. In
order to effect
final maturation, of the follicle and ovulation
in the absence of an
endogenous LH
surge, human chorionic gonadotropin
(hCG) must be given following the administration of Gonal-F®
when monitoring of the patient
indicates that sufficient follicular development
has occurred. There is interpatient variability in response
to FSH administration. The
physicochemical, immunological, and biological
activities of recombinant
FSH are comparable to those
of pituitary and human
menopausal urine-derived FSH.
Pharmacokinetics
Single dose pharmacokinetics
of r-hFSH were determined following intravenous subcutaneous and
intramuscular
administration
of 150 IU Gonal-F® to 12 healthy, down-regulated female
volunteers. Steady-state pharmacokinetics were also determined in
12 healthy down-regulated
female volunteers who
were administered a single daily dose
of 150 IU for seven days. These pharmacokinetics were confirmed
in pituitary down-regulated
women undergoing in vitro fertilization and embryo
transfer (IVF/ET),
treated with FSH doses of
up to 450 IU per day. The
pharmacokinetic parameters from these studies are included in Table
1.
Table 1: Pharmacokinetic parameters (mean ± SD) of
FSH following administration
of Gonal-F®
| Population |
Healthy female
volunteers
|
IVF/ET patients
|
|
Dose (IU)
|
Single Dose
IM
(50)
|
Single Dose
SC
(150)
|
Multiple Dose SC
(7 x 150)
|
Multiple dose
SC
(5 x 225)*
|
| AUC - (IU-hr/L) |
206 ± 66
|
176 ± 87
|
187 ± 61#
|
--
|
| Cmax (IU/L) |
3 ± 1
|
3 ± 1
|
9 ± 3
|
--
|
| tmax (hr)
|
25 ± 10
|
16 ± 10
|
8 ± 6
|
--
|
| t½
terminal (hr) |
50 ± 27
|
24 ± 11
|
24 ± 9
|
32**
|
| CL/F (L/hr) |
--
|
--
|
--
|
0.7 ± 0.2
|
| VssF/(L)
|
--
|
--
|
--
|
10 ± 3
|
| F (%) |
76 ± 30
|
66 ± 39
|
--
|
--
|
Abbreviations are:
- IVF/ET: in vitro fertilization/embryo transfer;
- Cmax : peak concentration
(above baseline);
- tmax time
of Cmax;
- CL/F: apparent
clearance;
- Vss/F: apparent
steady-state volume
of distribution;
- t½: absorption
half-life;
- F: bioavailability
compared to IV
- # - Steady-state AUC144-168 (After the 7th daily
SC dose)
- * - First five days of fixed regimen
followed by adjustment
of the dose depending on response
- ** - increases with body
mass index
Absorption: The absorption
rate of Gonal-F® following
subcutaneous or intramuscular
administration
was found to be slower than the elimination
rate. Hence the pharmacokinetics
of Gonal-F® are absorption rate-limited.
Distribution: Human tissue
or organ distribution
of FSH has not been determined for Gonal-F®
After intravenous
administration, the serum
profile of FSH
appears to be described by a two compartment open
model with a distribution
half-life of about 2-2.5 hours. Steady-state serum
levels were reached after 4 to 5 days of daily administration.
Metabolism/Excretion: FSH
metabolism following
administration of Gonal-F® has not been studied in humans. Total
clearance after IV
administration was 0.6 L/hr; mean
residence time was 17-20
hours. FSH renal clearance
was 0.07 L/hr after intravenous
administration
representing approximately 1/8 of total clearance.
Pharmacodynamics
Following daily subcutaneous
administration
of 150 IU of Gonal-F® for 7 days, serum
inhibin and estradiol,
and total follicular
volume responded as a
function of time, with
pronounced inter-individual variability. Pharmacodynamic effect
lagged behind FSH serum
concentration. Of the three pharmacodynamic parameters, serum
inhibin levels responded
with the least delay and declined rapidly after discontinuation
of Gonal-F®. Follicular growth
was most delayed and continued even after discontinuation of Gonal-F®
administration, and after serum
FSH levels had declined.
Maximum follicular
volume was better correlated
with either inhibin
or estradiol peak
levels than with FSH concentration. Inhibin rise was an early index
of follicular development.
Population Pharmacokinetics and Pharmacodynamics
To establish the pharmacokinetics
and pharmacodynamics
of FSH in a target population,
measurements performed during a clinical
study of in vitro fertilization/embryo transfer
were used in conjunction with pharmacokinetic data from studies
in healthy volunteers.
The apparent clearance
was comparable to that in healthy
volunteers. The absorption
rate was found to be influenced
by the body mass
index (BMI), suggesting
that the higher the BMI, the lower the rate
of absorption. However, FSH
serum levels following
fixed (during the first five days) and then adjusted doses of Gonal-F®
were found to be p.o. predictors
of follicular growth
rate. High pre-treatment serum FSH levels may predict lower follicular
growth rates.
Special populations: Safety, efficacy,
and pharmacokinetics of Gonal-F® in patients with renal
or hepatic insufficiency
have not been established.
Drug-Drug Interactions: No
drug/drug interaction studies have been conducted (see DRUG
INTERACTIONS).
Clinical Studies
The safety and efficacy
of Gonal-F® have been examined in four clinical studies, two
studies for ovulation
induction and two
studies for assisted reproductive technologies (ART). In
these comparative studies, there were no clinically significant
differences between treatment
groups in study outcomes.
Ovulation Induction
The safety and efficacy
of Gonal-F® administered subcutaneously vs. urofollitropin administered
intramuscularly were assessed in a phase III, open-label, randomized,
comparative, multinational, multicenter study in oligo-anovulatory
infertile women who failed to ovulate or conceive following adequate
clomiphene citrate therapy
(Study 5642).
The primary efficacy
parameter was the
ovulation rate. Two
hundred and twenty-two patients entered into the first cycle
of treatment, of whom
110 received Gonal-F® and 112 received urofollitropin. Ovulation
rates were similar between Gonal-F® and urofollitropin treatment
groups. The study results for the 222 patients who received treatment
in at least one cycle
are summarized in table
2.
Table 2: Cumulative Patient Ovulation and Clinical Pregnancy
Rates by Treatment Group in Ovulation Induction
|
Study 5642
|
Gonal-F®
(n= 110)
|
urofollitropin
(n= 112)
|
| Cumulative Ovulation
Rate |
| cycle 1 |
64%
|
59%
|
| cycle 2 |
78%
|
82%
|
| cycle 3 |
84%
|
91%
|
| Cumulative Clinical
Pregnancy* Rate |
| cycle 1 |
21%
|
21%
|
| cycle 2 |
28%
|
38%
|
| cycle 3 |
35%
|
46%
|
For the 90 patients who had a clinical
pregnancy (39 in Gonal-F®
group; 51 in urofollitropin group), the outcome
of the pregnancy w.s.
Table 3: Pregnancy Outcome by Treatment Group in Ovulation
Induction
|
Study 5642
|
Gonal-F®
(n= 39)
|
urofollitropin
(n= 51)
|
| Pregnancies not reaching
term |
20. 5%
|
13.7%
|
| Single births |
74. 4%
|
74. 5%
|
| Multiple births |
5.1%
|
11. 8%
|
A second randomized, comparative, open-label, multicenter study
was conducted in 23 U. S. centers (Study 5727). The primary
efficacy parameter
was ovulation rate.
Ovulation rates were similar between Gonal-F® and urofollitropin
treatment groups.
Two hundred and thirty-two patients with oligo-anovulatory infertility
received treatment
with up to three cycles of Gonal-F® administered subcutaneously
(118 patients) or urofollitropin administered intramuscularly (114
patients).
The cumulative patient
ovulation rate
and clinical pregnancy
rates by cycle are presented for the 232 patients who received treatment
in at least one cycle.
Table 4: Cumulative Patient Ovulation and Clinical Pregnancy
Rates by Treatment Group in Ovulation Induction
|
Study 5727
|
Gonal-F®
(n= 118)
|
urofollitropin
(n= 114)
|
| Cumulative Ovulation
Rate |
| cycle 1 |
58%
|
68%
|
| cycle 2 |
72%
|
86%
|
| cycle 3 |
81%
|
93%
|
| Cumulative Clinical
Pregnancy* Rate |
| cycle 1 |
13%
|
14%
|
| cycle 2 |
25%
|
25%
|
| cycle 3 |
37%
|
36%
|
For the 85 patients who had a clinical
pregnancy (44 in Gonal-F®
group; 41 in urofollitropin group), the outcome
of the pregnancy is
shown in Table 5.
Table 5: Pregnancy Outcome by Treatment Group in Ovulation
Induction
|
Study 5727
|
Gonal-F®
(n= 44)
|
urofollitropin
(n= 41)
|
| Pregnancies not reaching
term |
22. 7%
|
22. 0%
|
| Single births |
63. 6%
|
65.9%
|
| Multiple births |
13.7%
|
12. 2%
|
Assisted Reproductive Technologies (ART)
The safety and efficacy
of Gonal-F® administered subcutaneously vs. urofollitropin administered
intramuscularly were assessed in a phase III, open-label, randomized,
comparative, multinational, multicenter study in ovulatory, infertile
women undergoing stimulation
of multiple follicles
for In Vitro Fertilization and Embryo Transfer (IVF/ET) after
pituitary down-regulation with a GnRH agonist
(Study 5503). The purpose of the study was to demonstrate that Gonal-F®
administered subcutaneously, was clinically not different in terms
of safety and efficacy
from urofollitropin, administered intramuscularly. The initial
and maximal doses of Gonal-F® were 225 and 450 IU, respectively.
The primary efficacy
parameter was the
number of mature pre-ovulatory
follicles on the day of hCG administration. One hundred and twenty-three
patients were randomized and received either Gonal-F® (60 patients)
or urofollitropin (63 patients).
The results summarized in Table 6 are mean
data with Gonal-F® and urofollitropin administered to ovulatory
infertile women undergoing multiple follicular development
for IVF/ET.
Table 6: Treatment Outcomes by Treatment Group in ART
|
Study 5503
|
Gonal-F®
(n= 60)
|
urofollitropin
(n= 63)
|
| Mean number
of follicles ³ 14mm in diameter
on day of hCG |
7.8
|
9.2
|
| Mean number
of oocytes recovered per patient
|
9.3
|
10. 7
|
| Mean Serum E2 (pg/mL)
on day of hCG |
1576
|
2193
|
| Mean treatment
duration in days
(range) |
9.9 (5-20)
|
9.4 (5-14)
|
| Clinical pregnancy*
rate per attempt
|
20%
|
16%
|
| Clinical pregnancy*
rate per embryo transfer
|
24%
|
19%
|
For the 22 patients who had a clinical
pregnancy (12 in Gonal-F®
group; 10 in urofollitropin group), the outcome
of the pregnancy is
shown in Table 7.
Table 7: Pregnancy Outcome by Treatment Group in ART
|
Study 5503
|
Gonal-F®
(n= 12)
|
urofollitropin
(n= 10)
|
| Pregnancies not reaching
term |
25.0%
|
20.0%
|
| Single births |
41.7%
|
50.0%
|
| Multiple births |
33.3%
|
30.0%
|
A second randomized, comparative, open-label, multicenter study
was conducted in 7 U.S. centers (Study 5533). One hundred and fourteen
patients with ovulatory
infertility undergoing
IVF/ET were randomized and received either Gonal-F® by subcutaneous
administration
(56 patients) or urofollitropin by intramuscular
administration
(58 patients) following pituitary
down-regulation with a GnRH agonist. The primary
efficacy parameter
was the number of mature
preovulatory follicles on the day of hCG administration. Results
are summarized in table
8.
Table 8: Treatment Outcomes by Treatment Group in ART
|
Study 5533
|
Gonal-F®
(n= 56)
|
urofollitropin
(n= 58)
|
| Mean number
of follicles ³ 14mm in diameter
on day of hCG |
7.2
|
8.3
|
| Mean number
of oocytes recovered per patient
|
9.3
|
12. 3
|
| Mean Serum E2 (pg/mL)
on day of hCG |
1236
|
1513
|
| Mean treatment
duration in days
(range) |
10.0 (5-15)
|
9.0 (5-12)
|
| Clinical pregnancy*
rate per attempt
|
21%
|
22%
|
| Clinical pregnancy*
rate per embryo transfer
|
26%
|
25%
|
For the 25 patients who had a clinical
pregnancy (12 in Gonal-F®
group; 13 in urofollitropin group), the outcome
of the pregnancy is
shown in Table 9.
Table 9: Pregnancy Outcome by Treatment Group in ART
|
Study 5533
|
Gonal-F®
(n= 12)
|
urofollitropin
(n= 13)
|
| Pregnancies not reaching
term |
33. 3%
|
30. 8%
|
| Single births |
41 .7%
|
38. 5%
|
| Multiple births |
25. 0%
|
30.8%
|
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