Gonal-F (Follitropin Alfa) Drug Information: Clinical Pharmacology

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May 27, 2012

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Infertility »

What is infertility?

Infertility means not being able to get pregnant after one year of trying. Or, six months, if a woman is 35 or older. Women who can get pregnant but are unable to stay pregnant may also be infertile.

Pregnancy is the result of a process that has many steps. To get pregnant:

A woman must release an egg from one of her ovaries (ovulation).
The egg must go through a Fallopian tube toward the uterus (womb).
A man's sperm must join with (fertilize) the egg along the way.
The fertilized egg must attach to the inside of the uterus (implantation).

Infertility can happen if there are problems with any of these steps.

Is infertility a common problem?

Yes. About 10 percent of women (6.1 million) in the United States ages 15-44 have difficulty getting pregnant or staying pregnant, according to the Centers for Diseas...

Read the Infertility article »

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CLINICAL PHARMACOLOGY

Gonal-f®RFF (follitropin alfa for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Gonal-f® (follitropin alfa) RFF 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® (follitropin alfa) RFF when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration.

Pharmacokinetics

Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 IU Gonal-f® (follitropin alfa) RFF to 21 pre-menopausal healthy female volunteers who were pituitary down-regulated with a GnRH agonist.

The descriptive statistics for the pharmacokinetic parameters are presented in Table 1.

Table 1: Pharmacokinetic parameters of FSH following administration of Gonal-f® (follitropin alfa) RFF

Population Dose (IU)	Healthy Volunteers (n=21) 300 IU SC in a single dose
	Mean	%CV
AUClast (IU•hr/L)	884	20%
Cmax (IU/L)	9.83	23%
tmax (hr)	15.5	43%
t_½ (hr)	53	52%
Abbreviations are: Cmax: peak concentration (above baseline); tmax : time of Cmax; t_½: elimination half life

Absorption

The absorption rate of Gonal-f® (follitropin alfa) RFF following subcutaneous administration is slower than the elimination rate. Hence, the pharmacokinetics of Gonal-f® (follitropin alfa) RFF are absorption rate-limited.

Distribution

Human tissue or organ distribution of FSH has not been determined for Gonal-f® (follitropin alfa) RFF.

Metabolism/Excretion

FSH metabolism and excretion following administration of Gonal-f® (follitropin alfa) RFF have not been studied in humans.

Special populations

Safety, efficacy, and pharmacokinetics of Gonal-f® (follitropin alfa) RFF in patients with renal or hepatic insufficiency have not been established.

Drug-Drug Interactions

No drug-drug interaction studies have been conducted (see PRECAUTIONS).

Clinical Studies

The safety and efficacy of Gonal-f® (follitropin alfa) RFF have been examined in two clinical studies: one study (Study 22240) for ovulation induction and one study (Study 21884) for assisted reproductive technologies (ART).

Ovulation Induction (OI)

Study 22240 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women undergoing ovulation induction. Patients were randomized to either Gonal-f® (follitropin alfa) RFF (n=83), administered subcutaneously, or a comparator recombinant human FSH. The use of insulin-sensitizing agents was allowed during the study. Efficacy was assessed using the mean ovulation rate in the first cycle of treatment. The cycle 1 ovulation rate (primary outcome) for Gonal-f® (follitropin alfa) RFF is presented in Table 2. Additionally, this table includes cumulative secondary outcome results from cycle 1 through 3. Study 22240 was not powered to demonstrate differences in these secondary outcomes.

Table 2: Cumulative Ovulation and Clinical Pregnancy Rates in Ovulation Induction

Study 22240	Gonal-f® (follitropin alfa) RFF (n=83)
Cumulative^a Ovulation Rate
Cycle 1	72%^b
Cycle 2	89%^d
Cycle 3	92%^d
Cumulative^a Clinical Pregnancy^c Rate
Cycle 1	28%^d
Cycle 2	41%^d
Cycle 3	45%^d
^a Cumulative rates were determined per patient over cycles 1, 2, and 3. ^b Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis. ^c A clinical pregnancy was defined as a pregnancy during which a fetal sac (with orwithout heart activity) was visualized by ultrasound on day 34-36 after hCG administration. ^d Secondary efficacy parameter. Study 22240 was not powered to demonstrate differences in this parameter.

Assisted Reproductive Technologies (ART)

Study 21884 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for Assisted Reproductive Technologies (ART) after pituitary down-regulation with a GnRH agonist. Patients were randomized to either Gonal-f® (follitropin alfa) RFF (n=237), administered subcutaneously, or a comparator recombinant human FSH. Randomization was stratified by insemination technique [conventional in-vitro fertilization (IVF) vs. intra-cytoplasmic sperm injection (ICSI)]. Efficacy was assessed using the mean number of fertilized oocytes the day after insemination. The initial doses of Gonal-f® (follitropin alfa) RFF were 150 IU a day for patients < 35 years old and 225 IU for patients ≥ 35 years old. The maximal dose allowed for both age groups was 450 IU per day. Treatment outcomes for Gonal-f® (follitropin alfa) RFF are summarized in Table 3.

Table 3: Treatment Outcomes in ART

Study 21884	Gonal-f® RFF value (n)
Mean number of 2PN oocytes per patient	6.3 (237)^a
Mean number of 2PN oocytes per patient receiving IVF	6.1 (88)^b
Mean number of 2PN oocytes per patient receiving ICSI	6.5 (132)^b
Clinical pregnancy^c rate per attempt	33.5% (218)^d
Clinical pregnancy^c rate per embryo transfer	35.8% (204)^d
Mean treatment duration in days (range)	9.7 [3-21] (230)^d
^a Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis ^b Study 21884 was not powered to demonstrate differences in subgroups ^c A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 35-42 after hCG administration. ^d Secondary efficacy parameter. Study 21884 was not powered to demonstrate differences in this parameter