Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers
Abstract
The gonadotrophin-releasing hormone antagonist Cetrorelix is in advanced clinical development for the control of endogenous gonadotrophin secretion during the course of a fertility programme. The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of Cetrorelix following single and multiple s.c. administration of different doses. Thirty-six healthy female volunteers received either 0.25, 0.50 or 1.00 mg Cetrorelix, in a first menstrual cycle as single dose and in a second cycle as multiple dose (daily between cycle days 3 and 16). Frequent blood samples were collected for determination of Cetrorelix, follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Follicular growth was measured by transvaginal ultrasonography. After single administration of each dose, maximum Cetrorelix concentrations (Cmax) were reached after 1 h, and Cmax and area under curve (AUC) increased linearly with the dose. The median terminal half-life ranged from 5 to 10 h in the three different dose groups. FSH, LH, oestradiol and progesterone concentrations were suppressed, with a nadir at 6-12 h after Cetrorelix administration. During multiple administration, Cmax and AUC also showed dose-linearity. The median terminal half-life of Cetrorelix varied between 20 and 80 h. A dose-dependent suppression of FSH, LH and oestradiol concentrations was observed during treatment. After multiple administration, ovulation was delayed for 5, 10 and 13 days in the 0.25, 0.50 and 1.00 mg dose groups, respectively. In conclusion, Cetrorelix showed linear pharmacokinetics, and effectively delayed the LH surge.
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A modified menstrual cycle model based on the Margolskee 2011 model was used with optimal control theory to determine the minimum total exogenous estrogen/progesterone dose and timing of administration to induce anovulation.
“Utilized optimal control theory on a modified menstrual cycle model (based on Margolskee 2011 model) to determine the minimum total exogenous estrogen/progesterone dose and timing of administration to induce anovulation (absence of ovulation)”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [63]
The Discussion (page unavailable) says that ovulation was postponed, not prevented. The paper reports an experiment administering Cetrorelix to healthy volunteers, rather than using optimal control of exogenous estrogen and progesterone to induce anovulation. (LLM, conf=0.88)
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A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle
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- Authors
- Duijkers, I. J., Klipping, C., Willemsen, W. N., Krone, D., Schneider, E., Niebch, G., & Hermann, R.
- Affiliations
- Radboud University Nijmegen (NL)
- ORCID
- Klipping, C.
- Venue
- Human Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 1998-09-01
- Volume
- 13
- Issue
- 9
- Pages
- 2392-2398
- ISSN
- 0268-1161 (ISSN-L)
- 1460-2350
- OpenAlex
- W2133484074
- Cited by
- 114
- References
- 24
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 1 · 2021: 8 · 2020: 3 · 2019: 6 · 2018: 7 · 2017: 4 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Reproduction (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Keywords
- cetrorelix, GnRH antagonist, pharmacokinetics, pharmacodynamics, dose linearity, follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, ovulation delay, fertility control, folliculogenesis, healthy female volunteers
- MeSH terms
- Adolescent, Adult, Female, Fertilization in Vitro, Hormone Antagonists, Humans, Gonadotropin-Releasing Hormone, Ovulation Induction
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