Article (Scientific journals)
Comparison of Estetrol Exposure between Women and Mice to Model Preclinical Experiments and Anticipate Human Treatment.
Gallez, Anne; Nys, Gwenaël; Wuidar, Vincent et al.
2023In International Journal of Molecular Sciences, 24 (11), p. 9718
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Keywords :
estetrol; exposure; human; mice; pharmacokinetics; route of administration; Estetrol; Estrogens; Humans; Female; Mice; Animals; General Medicine
Abstract :
[en] Estetrol (E4) is a natural estrogen with promising therapeutic applications in humans. The European Medicines Agency and the Food and Drug Administration have approved the use of 15 mg E4/3 mg drospirenone for contraceptive indication. Phase III clinical trials with 15-20 mg E4 for the relief of climacteric complaints are currently running. Relevant data from preclinical animal models are needed to characterize the molecular mechanisms and the pharmacological effects of E4 and possibly to reveal new therapeutic applications and to anticipate potential adverse effects. Therefore, it is important to design experimental procedures in rodents that closely mimic or anticipate human E4 exposure. In this study, we compared the effects of E4 exposure after acute or chronic administration in women and mice. Women who received chronic E4 treatment per os at a dose of 15 mg once daily reached a steady state within 6 to 8 days, with a mean plasma concentration of 3.20 ng/mL. Importantly, with subcutaneous, intraperitoneal or oral administration of E4 in mice, a stable concentration over time that would mimic human pharmacokinetics could not be achieved. The use of osmotic minipumps continuously releasing E4 for several weeks provided an exposure profile mimicking chronic oral administration in women. Measurements of the circulating concentration of E4 in mice revealed that the mouse equivalent dose necessary to mimic human treatment does not fit with the allometric prediction. In conclusion, this study highlights the importance of precise definition of the most appropriate dose and route of administration to utilize when developing predictive preclinical animal models to mimic or anticipate specific human treatment.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Pharmacy, pharmacology & toxicology
Author, co-author :
Gallez, Anne ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Nys, Gwenaël;  Center for Interdisciplinary Research on Medicines (CIRM), Laboratory for the Analysis of Medicines, University of Liège, Avenue Hippocrate 15, 4000 Liège, Belgium
Wuidar, Vincent ;  Université de Liège - ULiège > GIGA
Dias Da Silva, Isabelle ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Taziaux, Mélanie ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie de la différenciation sexuelle du cerveau ; Mithra Pharmaceuticals, Rue Saint-Georges 5/7, 4000 Liège, Belgium
Kinet, Virginie ;  Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire ; Mithra Pharmaceuticals, Rue Saint-Georges 5/7, 4000 Liège, Belgium
Tskitishvili, Ekaterine  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Noël, Agnès ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Foidart, Jean-Michel  ;  Université de Liège - ULiège > Département des sciences cliniques
Piel, Géraldine  ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Fillet, Marianne  ;  Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Pequeux, Christel  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Language :
English
Title :
Comparison of Estetrol Exposure between Women and Mice to Model Preclinical Experiments and Anticipate Human Treatment.
Publication date :
03 June 2023
Journal title :
International Journal of Molecular Sciences
ISSN :
1661-6596
eISSN :
1422-0067
Publisher :
MDPI AG, Switzerland
Volume :
24
Issue :
11
Pages :
9718
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
ULiège - University of Liège [BE]
Télévie [BE]
SPW DGO6 - Service Public de Wallonie. Economie, Emploi, Recherche [BE]
Fonds Léon Fredericq [BE]
Estetra SRL [BE]
F.R.S.-FNRS - Fund for Scientific Research [BE]
Funding text :
Eurostars-Eureka program
Available on ORBi :
since 23 June 2023

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