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Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women.
Clin Pharmacol Ther 2000; 68(6):617-25CP

Abstract

PURPOSE

The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women.

BACKGROUND

Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the prevention of the premature ovulation indicated by an LH surge in in vitro fertilization. The pharmacokinetic and pharmacodynamic relationship for the suppression and the shift in the LH surge has not yet been established.

METHODS

In a placebo-controlled study, single subcutaneous doses of 1, 3, and 5 mg of cetrorelix were given to 36 subjects on day 8 of the natural menstrual cycle. Cetrorelix, LH, follicle-stimulating hormone, estradiol, and progesterone were determined.

RESULTS

Cetrorelix pharmacokinetics were described by a 2-compartment model with a terminal half-life of 56.9 +/- 27.1 hours. Mean shift in LH surge was by 4.1, 7.5, and 9.3 days with the 1-, 3-, and 5-mg doses, respectively. An indirect response sigmoid Emax model was developed for the suppression of LH and the shift in the LH surge. The inhibitory concentration of 50% (for LH suppression) and median effective concentration (for surge shift) estimates were 3.6 ng/mL and 1.6 ng/mL, respectively. The suppression of follicle-stimulating hormone was described by a similar Emax model, with an inhibitory concentration of 50% of 7.25 ng/mL.

CONCLUSIONS

A pharmacokinetic and pharmacodynamic model was developed for the transient initial suppression of LH and the subsequent shift in the LH surge after 3 single subcutaneous doses of cetrorelix without ovarian stimulation. A separate model was developed for the suppression of follicle-stimulating hormone by cetrorelix. The shift in the LH surge could be adequately described by the model.

Authors+Show Affiliations

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville 32610-0494, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

11180022

Citation

Nagaraja, N V., et al. "Pharmacokinetic and Pharmacodynamic Modeling of Cetrorelix, an LH-RH Antagonist, After Subcutaneous Administration in Healthy Premenopausal Women." Clinical Pharmacology and Therapeutics, vol. 68, no. 6, 2000, pp. 617-25.
Nagaraja NV, Pechstein B, Erb K, et al. Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women. Clin Pharmacol Ther. 2000;68(6):617-25.
Nagaraja, N. V., Pechstein, B., Erb, K., Klipping, C., Hermann, R., Niebch, G., & Derendorf, H. (2000). Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women. Clinical Pharmacology and Therapeutics, 68(6), pp. 617-25.
Nagaraja NV, et al. Pharmacokinetic and Pharmacodynamic Modeling of Cetrorelix, an LH-RH Antagonist, After Subcutaneous Administration in Healthy Premenopausal Women. Clin Pharmacol Ther. 2000;68(6):617-25. PubMed PMID: 11180022.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women. AU - Nagaraja,N V, AU - Pechstein,B, AU - Erb,K, AU - Klipping,C, AU - Hermann,R, AU - Niebch,G, AU - Derendorf,H, PY - 2001/2/17/pubmed PY - 2001/2/28/medline PY - 2001/2/17/entrez SP - 617 EP - 25 JF - Clinical pharmacology and therapeutics JO - Clin. Pharmacol. Ther. VL - 68 IS - 6 N2 - PURPOSE: The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women. BACKGROUND: Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the prevention of the premature ovulation indicated by an LH surge in in vitro fertilization. The pharmacokinetic and pharmacodynamic relationship for the suppression and the shift in the LH surge has not yet been established. METHODS: In a placebo-controlled study, single subcutaneous doses of 1, 3, and 5 mg of cetrorelix were given to 36 subjects on day 8 of the natural menstrual cycle. Cetrorelix, LH, follicle-stimulating hormone, estradiol, and progesterone were determined. RESULTS: Cetrorelix pharmacokinetics were described by a 2-compartment model with a terminal half-life of 56.9 +/- 27.1 hours. Mean shift in LH surge was by 4.1, 7.5, and 9.3 days with the 1-, 3-, and 5-mg doses, respectively. An indirect response sigmoid Emax model was developed for the suppression of LH and the shift in the LH surge. The inhibitory concentration of 50% (for LH suppression) and median effective concentration (for surge shift) estimates were 3.6 ng/mL and 1.6 ng/mL, respectively. The suppression of follicle-stimulating hormone was described by a similar Emax model, with an inhibitory concentration of 50% of 7.25 ng/mL. CONCLUSIONS: A pharmacokinetic and pharmacodynamic model was developed for the transient initial suppression of LH and the subsequent shift in the LH surge after 3 single subcutaneous doses of cetrorelix without ovarian stimulation. A separate model was developed for the suppression of follicle-stimulating hormone by cetrorelix. The shift in the LH surge could be adequately described by the model. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/11180022/Pharmacokinetic_and_pharmacodynamic_modeling_of_cetrorelix_an_LH_RH_antagonist_after_subcutaneous_administration_in_healthy_premenopausal_women_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9236&date=2000&volume=68&issue=6&spage=617 DB - PRIME DP - Unbound Medicine ER -