WO2001000227A1 - Gonadotropin releasing hormone antagonist - Google Patents
Gonadotropin releasing hormone antagonist Download PDFInfo
- Publication number
- WO2001000227A1 WO2001000227A1 PCT/EP2000/005643 EP0005643W WO0100227A1 WO 2001000227 A1 WO2001000227 A1 WO 2001000227A1 EP 0005643 W EP0005643 W EP 0005643W WO 0100227 A1 WO0100227 A1 WO 0100227A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antagonist
- gnrh
- gnrh antagonist
- amount
- ganirelix
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
Definitions
- the present invention relates to the use of GnRH antagonists in controlled ovarian hyperstimulation (COH) as well as to a method to prevent premature LH surge. It also relates to a cartridge comprising said antagonist and a kit comprising said cartridge and FSH.
- COH controlled ovarian hyperstimulation
- LH Luteinizing Hormone
- FSH Follicle Stimulating Hormone
- LH surge is a consequence of the raise in estrogen levels brought about by the endogenous secretion of LH and FSH.
- the estrogen is part of a positive feedback mechanism resulting in the elevated LH level.
- GnRH analogues are useful for a variety of disorders in which immediate reversible suppression of the pituitary-gonadal axis is desired. This can in principle be achieved with GnRH agonists as well as with GnRH antagonists. In comparison to GnRH agonists, GnRH antagonists have the advantage of not inducing an initial release of gonadotropins (flare-up) and steroids before suppression.
- GnRH agonists are clinically applied for the prevention of endogenous LH-surges during controlled ovarian hyperstimulation for Assisted Reproduction Techniques (ART).
- Specific disadvantages of GnRH agonists are the initial flare-up and the rather long period until pituitary suppression becomes effective.
- patients undergoing COH start only treatment with (recombinant) FSH after 2 to 3 weeks pretreatment with GnRH agonists.
- GnRH antagonists by GnRH receptor competition provide an immediate inhibition of gonadotropin secretion, especially of LH.
- GnRH antagonist treatment is only required during the few days when there is an increased risk for a premature LH surge.
- the GnRH antagonist dosage range is critical: too low a GnRH antagonist dosage leading to prmature LH rises, while too high a GnRH antagonist dosage hampered follicular maturation.
- the antagonist ganirelix for example a fixed amount being at least 0.125 mg but less than 1 mg and preferably about 0.25 mg was suggested (W098/58657).
- the invention therefore relates to a pharmaceutical preparation comprising GnRH antagonist, while applying a dosage adjusted for body weight sufficient to prevent a premature LH surge and ensuring successful treatment outcome.
- Such preparation is useful in the treatment of women undergoing COH.
- a preferred antagonist according to the present invention is ganirelix which has the following chemical name:
- the abbreviated structure is [N- Ac-D-Na(2) 1 ,D-pCIPhe ,D-Pal(3) 3 ,D-hArg(Et 2 ) 6 ,L-hArg(Et 2 ) 8 ,D-Ala 10 -GnRH.
- the GnRH antagonist ganirelix is disclosed in US patent No. 4,801 ,577 for nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists. This patent, which is fully incorporated herein by reference, describes the method for the preparation of these compounds. It is indicated that the compounds described therein can be used for the prevention of ovarian hyperstimulation.
- a daily range is suggested for administration of the active ingredient between 0.001 and 5 mg/kg body weight, preferably between 0.01 and 1 mg/kg.
- the preparation is administered together with FSH during the days of ovarian stimulation when a premature LH rise may easily occur e.g. from day 5 of FSH administration onwards.
- the preparation in its proposed dosage range has the advantage of providing an immediate effect that prevents an LH surge and at the same time maximizes the chances of establishing pregnancy.
- Administration is usually stopped when sufficient follicles have matured and exogenous hCG/LH is given for induction of ovulation.
- the amount of hCG/LH usually amounts 5000-10000 IU.
- induction of ovulation can be performed by administration of a GnRH agonist.
- the agonist instead of hCG/LH is usually given on the same day in an amount sufficient to trigger ovulation.
- Suitable range is 10-1000 ⁇ g.
- Suitable agonists are e.g. buserelin, triptorelin and luprorelin.
- the exact regimen for administration might depend on the individual response and is finally to be decided by the clinician who treats the subject. For this reason the duration of initial ovarian stimulation with FSH alone as well as the duration of combined treatment with FSH/GnRH antagonist treatment may vary.
- FSH treatment usually starts at menses day 1 , 2 or 3.
- Ovarian stimulation with FSH alone may be continued up to 5 days in an amount of e.g. 150-225 IU.
- FSH is administered preferably as a recombinant protein.
- Treatment with GnRH antagonist may be started at the first day of FSH, but preferably such treatment starts at FSH treatment day 4 or 5.
- the GnRH antagonist is administered in the previously determined amount according to the invention in combination with FSH in amounts between 50 - 600 IU, preferably between 100 - 300 IU.
- GnRH antagonist treatment may last 2 - 14 days i.e. up to the moment whereupon the patient is treated with exogenous LH/hCG or a GnRH or GnRH agonist for ovulation induction.
- ganirelix in an amount according to Formula I is used for the manufacture of a medicament to prevent a premature LH surge in women undergoing controlled ovarian hyperstimulation.
- the pharmaceutical preparations for use according to the invention can be prepared in accordance with standard techniques such as for example are described in the standard reference, Gennaro et al. (Ed.), Remmington's Pharmaceutical Sciences, (18 th ed. Mack Publishing Company, 1990, e.g. Part 8: Pharmaceutical Preparations And Their Manufacture).
- the active substance is mixed with or dissolved in a pharmaceutical acceptable carrier. Any conventional pharmaceutical carrier that does not interfere with performance of the active ingredient can be used in the preparations according to the present invention.
- Formulations may contain as common excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphtalenes and the like.
- the pharmaceutical preparation of the antagonist may be administered parenterally. Preferably it is administered subcutaneously, particularly in the form of liquid solutions or suspensions.
- a typical formulation is a solution containing, in addition to the active substance in an amount as indicated above, glacial acetic acid, mannitol, and water adjusted to pH 5 with sodium hydroxide and / or hydrochloric acid.
- preservations such as e.g. methyl- and propylparaben or benzylalcohol can be added.
- the solutions can be packaged e.g. in glass vials, cartridges or in syringes.
- a cartridge containing a sterile liquid formulation of ganirelix.
- a cartridge means a closed container, such as an ampoule, a vial, a bottle or a bag comprising an amount of GnRH antagonist so as to administer accurately and preferably repeatedly to a patient a dosage of GnRH antagonist according to Formula I.
- a cartridge may contain an amount of the liquid antagonist formulation corresponding to one or more therapeutic dosages of the antagonist. Preferably these dosages are to be applied in a single regimen.
- the cartridges contain an amount of GnRH antagonist sufficient for 5 administrations.
- the cartridges are preferably used in combination with a device making it possible to deliver adjustable dosages needed in the regimen.
- a device for administration comprising a cartridge containing a sterile liquid formulation according to the invention.
- a preferred device for administration is a pen-type injector, which comprise means for easy adjustment of the amount of a formulation that is to be injected.
- pen type injectors are known per se, such as for instance the well known B-D Pen (a trademark of Becton Dickinson and Company), an insulin-injection system.
- Adjustable cartridges according to the invention have the advantage of accurate self-administration thereby increasing the convenience for the patients.
- kits for use in controlled ovarian hyperstimulation in female patients Such a kit comprises a GnRH antagonist in a dosage form and quantity so as to accurately administer to a patient in an amount according to Formula I, in a frequency effective to prevent a premature LH surge.
- the kit comprises FSH in a dosage form and quantity suitable for administering in an amount and frequency effective to stimulate growth of follicles.
- the kit may comprise also hCG/LH or GnRH agonists in a dosage form and quantity suitable for administering in an amount and frequency effective to induce ovulation.
- the GnRH antagonist preferably is packaged in a cartridge. This cartridge preferably is to be used in combination with a device for administration such as a pen type injector allowing an adjustable and accurate administration of GnRH antagonist.
- the kit might also comprise a pen type injector system.
- FIG. 1 LH levels were measured at the start (just before the first injection of ganirelix) and end of ganirelix treatment.
- the graph shows the pregnancies in relation to the various levels. LH levels are indicated in IU/L.
- Figure 2 Area under the curve of ganirelix versus body weight of subjects in three pharmacokinetic studies. Circles mean protocol A; triangles mean protocol B and squares mean protocol C.
- Figure 3 Chance of pregnancy versus body weight; results from Phase III efficacy study. Dots in the top of the graph correspond to pregnant subjects
- Recombinant FSH (recFSH) treatment was started on day 2 or 3 of the menstrual cycle by a once daily SC injection. Just prior to the first injection of recFSH an hCG test was performed to exclude pregnancy, a blood sample for hormone analysis was taken and an ultrasonography (USS) was performed. During recFSH treatment day 1 through 5, the daily dose of recFSH was fixed to 150 international units (IU). On day 6 of recFSH treatment ganirelix treatment was started by daily SC administration until and including the day before the day of hCG.
- the dose of recFSH was adjusted depending on the individual ovarian response as assessed by USS. From the first day of ganirelix i.e. from recFSH treatment day 6 onwards up to and including the day of hCG, a blood sample for hormone analysis was taken prior to drug administration. And an USS was performed, at least every two days.
- LH levels were assessed by a standard LH specific assay at the Central Laboratory of the Analytisch Biochemisch Laboratorium (Assen, The Netherlands). From the data on LH levels, a plot was constructed in order to investigate the possible role of LH on pregnancy.
- LH levels were measured at the start (just before the first injection of ganirelix) and end of ganirelix treatment.
- Figure 1 shows the pregnancies in relation to the various levels.
- Protocol A an open-label two-way crossover study to assess the absolute bioavailablity of 0.25 mg ganirelix after single injection.
- Protocol B an open-label randomized, multiple dose parallel-design study to assess the dose- proportionality and the pharmacokinetic properties of ganirelix (0.125 , 0.25 and 0.5 mg) after repeated subcutaneous administration.
- Protocol C an open, randomized, two-way crossover study to establish the local tolerance and bioavailability of ganirelix after multiple subcutaneous administration (2 mg).
- Pharmaco-statistical models have been set up to describe the influence of body weight on the effectiveness of ganirelix for both the prevention of LH- rises and pregnancy outcome.
- Spline functions have been applied to give the best and assumptionless mathematical description of the available data. Using these models optimal doses with respect to the prevention of LH-rises and pregnancy have been determined for different body weights.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001505935A JP2003503358A (en) | 1999-06-23 | 2000-06-19 | Gonadotropin-releasing hormone antagonists |
CA002341974A CA2341974A1 (en) | 1999-06-23 | 2000-06-19 | Gonadotropin releasing hormone antagonist |
AU62638/00A AU6263800A (en) | 1999-06-23 | 2000-06-19 | Gonadotropin releasing hormone antagonist |
EP00949193A EP1140132A1 (en) | 1999-06-23 | 2000-06-19 | Gonadotropin releasing hormone antagonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99202027 | 1999-06-23 | ||
EP99202027.1 | 1999-06-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001000227A1 true WO2001000227A1 (en) | 2001-01-04 |
Family
ID=8240349
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/005643 WO2001000227A1 (en) | 1999-06-23 | 2000-06-19 | Gonadotropin releasing hormone antagonist |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1140132A1 (en) |
JP (1) | JP2003503358A (en) |
AR (1) | AR024438A1 (en) |
AU (1) | AU6263800A (en) |
CA (1) | CA2341974A1 (en) |
WO (1) | WO2001000227A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003103770A2 (en) * | 2002-06-07 | 2003-12-18 | Pantarhei Bioscience B.V. | Method of controlled ovarian hyperstimulation and pharmaceutical kit for use in such method |
WO2012042381A1 (en) * | 2010-09-29 | 2012-04-05 | Ferring B.V. | Composition for controlled ovarian stimulation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998055470A1 (en) * | 1997-06-05 | 1998-12-10 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
WO1998058657A1 (en) * | 1997-06-20 | 1998-12-30 | Akzo Nobel N.V. | Gonadotropin releasing hormone antagonist |
-
2000
- 2000-06-19 WO PCT/EP2000/005643 patent/WO2001000227A1/en not_active Application Discontinuation
- 2000-06-19 AU AU62638/00A patent/AU6263800A/en not_active Abandoned
- 2000-06-19 EP EP00949193A patent/EP1140132A1/en not_active Withdrawn
- 2000-06-19 CA CA002341974A patent/CA2341974A1/en not_active Abandoned
- 2000-06-19 JP JP2001505935A patent/JP2003503358A/en not_active Withdrawn
- 2000-06-22 AR ARP000103116A patent/AR024438A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998055470A1 (en) * | 1997-06-05 | 1998-12-10 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
WO1998058657A1 (en) * | 1997-06-20 | 1998-12-30 | Akzo Nobel N.V. | Gonadotropin releasing hormone antagonist |
Non-Patent Citations (3)
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003103770A2 (en) * | 2002-06-07 | 2003-12-18 | Pantarhei Bioscience B.V. | Method of controlled ovarian hyperstimulation and pharmaceutical kit for use in such method |
WO2003103770A3 (en) * | 2002-06-07 | 2004-04-22 | Ares Trading Sa | Method of controlled ovarian hyperstimulation and pharmaceutical kit for use in such method |
EA009371B1 (en) * | 2002-06-07 | 2007-12-28 | Арес Трейдинг С.А. | Method of controlled ovarian hyperstimulation pharmaceutical kit for use in such method |
US7815912B2 (en) | 2002-06-07 | 2010-10-19 | Ares Trading, S.A. | Method of controlled ovarian hyperstimulation and pharmaceutical kit for use in such method |
WO2012042381A1 (en) * | 2010-09-29 | 2012-04-05 | Ferring B.V. | Composition for controlled ovarian stimulation |
EP2842567A1 (en) * | 2010-09-29 | 2015-03-04 | Ferring B.V. | Composition for controlled ovarian stimulation |
EP2621517B1 (en) | 2010-09-29 | 2015-06-17 | Ferring B.V. | Composition for use in treating infertility |
US9320778B2 (en) | 2010-09-29 | 2016-04-26 | Ferring B.V. | Method for controlled ovarian stimulation with combined FSH and hCG |
US10064920B2 (en) | 2010-09-29 | 2018-09-04 | Ferring B.V. | Method for controlled ovarian stimulation using FSH and hCG |
Also Published As
Publication number | Publication date |
---|---|
AU6263800A (en) | 2001-01-31 |
JP2003503358A (en) | 2003-01-28 |
CA2341974A1 (en) | 2001-01-04 |
AR024438A1 (en) | 2002-10-02 |
EP1140132A1 (en) | 2001-10-10 |
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