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
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.
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]
Hagen A.A. Barr M. Diczfalusy E. Metabolism of 17-Beta-Oestradiol-4-14-C in Early Infancy Acta Endocrinol. 1965 49 207 220
Coelingh Bennink H.J. Skouby S. Bouchard P. Holinka C.F. Ovulation inhibition by estetrol in an in vivo model Contraception 2008 77 186 190 10.1016/j.contraception.2007.11.014 18279689
Holinka C.F. Diczfalusy E. Coelingh Bennink H.J. Estetrol: A unique steroid in human pregnancy J. Steroid Biochem. Mol. Biol. 2008 110 138 143 10.1016/j.jsbmb.2008.03.027
Holinka C.F. Brincat M. Coelingh Bennink H.J. Preventive effect of oral estetrol in a menopausal hot flush model Climacteric 2008 11 (Suppl. S1) 15 21 10.1080/13697130701822807
Pluchino N. Santoro A.N. Casarosa E. Giannini A. Genazzani A. Russo M. Russo N. Petignat P. Genazzani A.R. Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats J. Steroid Biochem. Mol. Biol. 2014 143 285 290 10.1016/j.jsbmb.2014.04.011 24787659
Pluchino N. Drakopoulos P. Casarosa E. Freschi L. Petignat P. Yaron M. Genazzani A.R. Effect of estetrol on Beta-Endorphin level in female rats Steroids 2015 95 104 110 10.1016/j.steroids.2015.01.003
Tskitishvili E. Nisolle M. Munaut C. Pequeux C. Gerard C. Noel A. Foidart J.M. Estetrol attenuates neonatal hypoxic-ischemic brain injury Exp. Neurol. 2014 261C 298 307 10.1016/j.expneurol.2014.07.015
Tskitishvili E. Pequeux C. Munaut C. Viellevoye R. Nisolle M. Noel A. Foidart J.M. Use of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury: To combine or not to combine? Oncotarget 2016 7 33722 33743 10.18632/oncotarget.9591
Tskitishvili E. Pequeux C. Munaut C. Viellevoye R. Nisolle M. Noel A. Foidart J.M. Estrogen receptors and estetrol-dependent neuroprotective actions: A pilot study J. Endocrinol. 2017 232 85 95 10.1530/JOE-16-0434
Benoit T. Valera M.C. Fontaine C. Buscato M. Lenfant F. Raymond-Letron I. Tremollieres F. Soulie M. Foidart J.M. Game X. et al. Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor alpha Activation Am. J. Pathol. 2017 187 2499 2507 10.1016/j.ajpath.2017.07.013
Abot A. Fontaine C. Buscato M. Solinhac R. Flouriot G. Fabre A. Drougard A. Rajan S. Laine M. Milon A. et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation EMBO Mol. Med. 2014 6 1328 1346 10.15252/emmm.201404112 25214462
Buscato M. Davezac M. Zahreddine R. Adlanmerini M. Metivier R. Fillet M. Cobraiville G. Moro C. Foidart J.M. Lenfant F. et al. Estetrol prevents Western diet-induced obesity and atheroma independently of hepatic estrogen receptor alpha Am. J. Physiol. Endocrinol. Metab. 2021 320 E19 E29 10.1152/ajpendo.00211.2020 33135461
Montt-Guevara M.M. Giretti M.S. Russo E. Giannini A. Mannella P. Genazzani A.R. Genazzani A.D. Simoncini T. Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells Front. Endocrinol. 2015 6 111 10.3389/fendo.2015.00111 26257704
Montt-Guevara M.M. Palla G. Spina S. Bernacchi G. Cecchi E. Campelo A.E. Shortrede J.E. Canu A. Simoncini T. Regulatory effects of estetrol on the endothelial plasminogen pathway and endothelial cell migration Maturitas 2017 99 1 9 10.1016/j.maturitas.2017.02.005
Davezac M. Zahreddine R. Buscato M. Smirnova N.F. Febrissy C. Laurell H. Gilardi-Bresson S. Adlanmerini M. Liere P. Flouriot G. et al. The different natural estrogens promote endothelial healing through distinct cell targets JCI Insight 2023 8 e161284 10.1172/jci.insight.161284
Seeger H. Hadji P. Mueck A.O. Endogenous estradiol metabolites stimulate the in vitro proliferation of human osteoblastic cells Int. J. Clin. Pharm. 2003 41 148 152 10.5414/CPP41148
Coelingh Bennink H.J. Heegaard A.M. Visser M. Holinka C.F. Christiansen C. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model Climacteric 2008 11 (Suppl. S1) 2 14 10.1080/13697130701798692
Gerard C. Blacher S. Communal L. Courtin A. Tskitishvili E. Mestdagt M. Munaut C. Noel A. Gompel A. Pequeux C. et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation J. Endocrinol. 2015 224 85 95 10.1530/JOE-14-0549
Gallez A. Blacher S. Maquoi E. Konradowski E. Joiret M. Primac I. Gerard C. Taziaux M. Houtman R. Geris L. et al. Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer Cancers 2021 13 2486 10.3390/cancers13102486
Gerard C. Mestdagt M. Tskitishvili E. Communal L. Gompel A. Silva E. Arnal J.F. Lenfant F. Noel A. Foidart J.M. et al. Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms Oncotarget 2015 6 17621 17636 10.18632/oncotarget.4184
Devineni D. Skee D. Vaccaro N. Massarella J. Janssens L. LaGuardia K.D. Leung A.T. Pharmacokinetics and pharmacodynamics of a transdermal contraceptive patch and an oral contraceptive J. Clin. Pharm. 2007 47 497 509 10.1177/0091270006297919 17389559
Devissaguet J.P. Brion N. Lhote O. Deloffre P. Pulsed estrogen therapy: Pharmacokinetics of intranasal 17-beta-estradiol (S21400) in postmenopausal women and comparison with oral and transdermal formulations Eur. J. Drug. Metab. Pharm. 1999 24 265 271 10.1007/BF03190030
Zanella E.R. Grassi E. Trusolino L. Towards precision oncology with patient-derived xenografts Nat. Rev. Clin. Oncol. 2022 19 719 732 10.1038/s41571-022-00682-6 36151307
Visser M. Holinka C.F. Coelingh Bennink H.J. First human exposure to exogenous single-dose oral estetrol in early postmenopausal women Climacteric 2008 11 (Suppl. S1) 31 40 10.1080/13697130802056511
Gerard C. Arnal J.F. Jost M. Douxfils J. Lenfant F. Fontaine C. Houtman R. Archer D.F. Reid R.L. Lobo R.A. et al. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause Expert. Rev. Clin. Pharm. 2022 15 121 137 10.1080/17512433.2022.2054413 35306927
Kluft C. Zimmerman Y. Mawet M. Klipping C. Duijkers I.J.M. Neuteboom J. Foidart J.M. Bennink H.C. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol Contraception 2017 95 140 147 10.1016/j.contraception.2016.08.018 27593335
Douxfils J. Klipping C. Duijkers I. Kinet V. Mawet M. Maillard C. Jost M. Rosing J. Foidart J.M. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters Contraception 2020 102 396 402 10.1016/j.contraception.2020.08.015
Duijkers I. Klipping C. Kinet V. Jost M. Bastidas A. Foidart J.M. Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function Contraception 2021 103 386 393 10.1016/j.contraception.2021.03.003
Klipping C. Duijkers I. Mawet M. Maillard C. Bastidas A. Jost M. Foidart J.M. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone Contraception 2021 103 213 221 10.1016/j.contraception.2021.01.001
Fruzzetti F. Fidecicchi T. Montt Guevara M.M. Simoncini T. Estetrol: A New Choice for Contraception J. Clin. Med. 2021 10 5625 10.3390/jcm10235625
Apter D. Zimmerman Y. Beekman L. Mawet M. Maillard C. Foidart J.M. Coelingh Bennink H.J.T. Estetrol combined with drospirenone: An oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control Eur. J. Contracept. Reprod. Health Care 2017 22 260 267 10.1080/13625187.2017.1336532 28641030
Apter D. Zimmerman Y. Beekman L. Mawet M. Maillard C. Foidart J.M. Coelingh Bennink H.J. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: Results from a phase II, randomised, dose-finding study (FIESTA) Contraception 2016 94 366 373 10.1016/j.contraception.2016.04.015 27153745
Gemzell-Danielsson K. Apter D. Zatik J. Weyers S. Piltonen T. Suturina L. Apolikhina I. Jost M. Creinin M.D. Foidart J.M. Estetrol-Drospirenone combination oral contraceptive: A clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia BJOG 2022 129 63 71 10.1111/1471-0528.16840 34245666
Creinin M.D. Westhoff C.L. Bouchard C. Chen M.J. Jensen J.T. Kaunitz A.M. Achilles S.L. Foidart J.M. Archer D.F. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results Contraception 2021 104 222 228 10.1016/j.contraception.2021.05.002
Lee A. Syed Y.Y. Estetrol/Drospirenone: A Review in Oral Contraception Drugs 2022 82 1117 1125 10.1007/s40265-022-01738-8
Kaunitz A.M. Achilles S.L. Zatik J. Weyers S. Piltonen T. Suturina L. Apolikhina I. Bouchard C. Chen M.J. Jensen J.T. et al. Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women Contraception 2022 116 29 36 10.1016/j.contraception.2022.07.010
Coelingh Bennink H.J.T. Verhoeven C. Zimmerman Y. Visser M. Foidart J.M. Gemzell-Danielsson K. Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: Results from a multiple-rising-dose study Menopause 2017 24 677 685 10.1097/GME.0000000000000823 28169916
Kuhl H. Pharmacology of estrogens and progestogens: Influence of different routes of administration Climacteric 2005 8 (Suppl. S1) 3 63 10.1080/13697130500148875 16112947
Nair A.B. Jacob S. A simple practice guide for dose conversion between animals and human J. Basic. Clin. Pharm. 2016 7 27 31 10.4103/0976-0105.177703
Nys G. Gallez A. Kok M.G.M. Cobraiville G. Servais A.C. Piel G. Pequeux C. Fillet M. Whole blood microsampling for the quantitation of estetrol without derivatization by liquid chromatography-tandem mass spectrometry J. Pharm. Biomed. Anal. 2017 140 258 265 10.1016/j.jpba.2017.02.060