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.
Ganirelix Acetate 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 Ganirelix Acetate is more pronounced than that of FSH. An initial release of endogenous gonadotropins has not been detected with Ganirelix Acetate, which is consistent with an antagonist effect. Upon discontinuation of Ganirelix Acetate, pituitary LH and FSH levels are fully recovered within 48 hours.
Pharmacokinetics
The pharmacokinetic parameters of single and multiple injections of 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 µ g.
TABLE I: Mean (SD) pharmacokinetic parameters of 250 µg of Ganirelix Acetate following a single subcutaneous (SC) injection (n=15) and daily SC injections (n=15) for seven days. | tmax
h | t1/2
h | Cmax
ng/mL | AUC
ng•h/mL | CL/F
L/h | Vd/F
L |
| tmax Time to maximum concentration |
| t1/2 Elimination half-life |
| Cmax Maximum serum concentration |
| AUC Area under the curve; Single dose: AUC0–∞; multiple dose: AUC0–24 |
| Vd Volume of distribution |
| CL Clearance = Dose/AUC0–∞ |
| F Absolute bioavailability |
| Ganirelix Acetate single dose | 1.1 (0.3) | 12.8 (4.3) | 14.8 (3.2) | 96 (12) | 2.4 (0.2)
| 43.7 (11.4) |
| Ganirelix Acetate 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) |
Absorption
Ganirelix Acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Ganirelix Acetate following a single 250 µ g subcutaneous injection to healthy female volunteers is 91.1%.
Distribution
The mean (SD) volume of distribution of Ganirelix Acetate in healthy females following intravenous administration of a single 250 µ g 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 Ganirelix Acetate to healthy female volunteers, Ganirelix Acetate 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. Ganirelix Acetate is not found in the feces. The 1–4 peptide and 1–6 peptide of Ganirelix Acetate are the primary metabolites observed in the feces.
Excretion
On average, 97.2% of the total radiolabeled Ganirelix Acetate 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 [14C]-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 Injection 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 Ganirelix Acetate 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 Ganirelix Acetate Injection was established in two adequate and well-controlled clinical studies which included women with normal endocrine and pelvic ultrasound 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. Ganirelix Acetate Injection 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 Ganirelix Acetate. Both recombinant FSH and Ganirelix Acetate 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, Ganirelix Acetate 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 Ganirelix Acetate Injection were evaluated for the prevention of LH surges in women undergoing COH with recombinant FSH. Ganirelix Acetate Injection doses ranging from 62.5 µ g to 2000 µ g 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 Ganirelix Acetate. Median serum E2 (17 b -estradiol) on the day of hCG administration was 1475, 1110, and 1160 pg/mL for the 62.5, 125, and 250 µ g doses, respectively. Lower peak serum E2 levels of 823, 703, and 441 pg/mL were seen at higher doses of Ganirelix Acetate 500, 1000, and 2000 µ g, respectively. The highest pregnancy and implantation rates were achieved with the 250 µ g dose of Ganirelix Acetate Injection as summarized in Table II.
TABLE II: Results from the multicenter, double-blind, randomized, dose-finding study to assess the efficacy of Ganirelix Acetate Injection to prevent premature LH surges in women undergoing COH with recombinant FSH. | Daily dose (µ g)of Ganirelix Acetate Injection |
| 62.5 µ g | 125 µ g | 250 µ g | 500 µ g | 1000 µ g | 2000 µ g |
| (Protocol 38602) |
No. subjects receiving
Ganirelix Acetate | 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
5th–95th percentiles
| 3.6
0.6–19.9 | 2.5
0.6–11.4 | 1.7
< 0.25–6.4 | 1.0
0.4–4.7 | 0.6
< 0.25–2.2 | 0.3
< 0.25–0.8 |
Serum E2 (pg/mL)on day of hCG
5th–95th percentiles | 1475
645–3720 | 1110
424–3780 | 1160
384–3910 | 823
279–2720 | 703
284–2360 | 441
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 (%)
| 14.2 (26.8) | 16.3 (30.5) | 21.9 (30.6) | 9.0 (23.7) | 8.5 (21.7) | 4.9 (20.1) |
Transient LH rises alone were not deleterious to achieving pregnancy with Ganirelix Acetate at doses of 125 µ g (3/6 subjects) and 250 µ g (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 Ganirelix Acetate Injection in women undergoing COH. Follicular phase treatment with Ganirelix Acetate 250 µ g was studied using a luteal phase GnRH agonist as a reference treatment. A total of 463 subjects were treated with Ganirelix Acetate 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 Ganirelix Acetate arm are summarized in Table III.
TABLE III: Results from the multicenter, open-label, randomized study to assess the efficacy and safety of Ganirelix Acetate Injection in women undergoing COH. | Ganirelix Acetate 250 µ g |
| (Protocol 38607) |
| No. subjects treated | 463 |
Duration of GnRH analog (days)
| 5.4 (2.0) |
Duration of recombinant FSH (days)
| 9.6 (2.0) |
Serum E2 (pg/mL)on day of hCG
5th–95th percentiles | 1190
373–3105 |
Serum LH (mIU/mL) on day of hCG
5th–95th percentiles | 1.6
0.6–6.9 |
| No. of subjects with LH rise ≥ 10 mIU/mL
| 13 |
No. of follicles > 11 mm
| 10.7 (5.3) |
| No. of subjects with oocyte retrieval | 440 |
| No. of oocytes | 8.7 (5.6) |
| Fertilization rate | 62.1% |
| No. subjects with ET
| 399 |
| No. of embryos transferred | 2.2 (0.6) |
| No. of embryos | 6.0 (4.5) |
| Ongoing pregnancy rate
| |
| per attempt, n (%)
| 94 (20.3) |
| per transfer, n (%) | 93 (23.3) |
| Implantation rate (%) | 15.7 (29) |
Some centers were limited to the transfer of ≤ 2 embryos based on local practice standards
The mean number of days of Ganirelix Acetate 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 Ganirelix Acetate Injection 250 µ g, 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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