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A single-dose and 3-month clinical—pharmacokinetic study with a new combination oral contraceptive

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Advances in Contraception

Abstract

The study was performed in 14 young women. The combination oral contraceptive contained 75 μg gestodene (GSD) and 20 μg ethinyl estradiol (EE2) per dosage unit. The volunteers received a single dose on day 21 of a treatment-free precycle (PCd21) and, after a washout period of 7 days, used the preparation in a 21 d/7 d schedule for three months. Daily drug serum level profiles were taken on PCd21 and on days 1 and 21 of treatment cycles 1 and 3. In addition, trough drug serum levels were followed every other day during treatment cycles 1 and 3. Serum levels of GSD, EE2, CBG, SHBG and testosterone (T) were determined by means of specifically developed or commercially available RIAs. Pharmacokinetic evaluation was carried out with TOPFIT and parameters were evaluated for differences with thet-test. Main target variables wereC max,t max and AUC for EE2, GSD and unbound GSD on day 21, cycle 3 vs. PCd21.

EE2 pharmacokinetics were in agreement with a dose of 20 μg/unit. Single-doseC max of 65 pg/ml and AUC of 612 pg h ml−1 increased by 40–60% during treatment cycles as a result of accumulation. EE2 induced basal SHBG (102 nmol/L) and CBG (42 μg/ml) serum levels to about 220 nmol/L and 87 μg/ml, respectively, at the end of treatment cycles 1 and 3.

Serum T levels dropped to 50% of baseline levels during treatment cycles and free T concentrations were reduced by 60–70%. GSD pharmacokinetics at the end of treatment cycles 1 and 3 were different from single-dose pharmacokinetics. Single-doseC max of 3.5 ng/ml and AUC0–24 h of 22 ng h ml−1 increased to steady-state levels of 8–8.7 ng/ml and 90–106 ng h ml−1, respectively. The increase in GSD levels under treatment is the result of two parallel processes, i.e. accumulation and enlargement of the specific binding compartment. This was shown by protein-binding experiments, demonstrating an increase in specific (SHBG) binding from 69% to 80% and a reduction in the free fraction of GSD by 40% during treatment.

The results of GSD and EE2 pharmacokinetics obtained in the present study confirm previous results with Femodene, when the reduction in the EE2 dose by 10 μg/d is taken into account.

Resumé

Cette étude a été réalisée sur 14 jeunes femmes. Le contraceptif oral combiné contenait 75 μg de gestodène (GSD) et 20 μg d'éthinyl oestradiol (EE2) par dose unitaire. Les volontaires ont reçu une dose unique au vingt et unième jour du cycle préliminaire sans traitement (CPj21) et — après une période de 7 jours de sevrage — elles ont absorbé la préparation selon une posologie de 2lj/7j pendant trois mois. Les profils journaliers du taux sérique du produit ont été établis au jour CPj21 et aux jours 1 et 21 des cycles de traitement 1 et 3. En outre, on a suivi tous les deux jours, durant les cycles 1 et 3 du traitment, les taux sériques inférieurs du produit. On a déterminé, selon des méthodes de RIA spécifiquement mises au point ou commercialement disponibles, les taux sériques de GSD, EE2, CBG, SHBG et testostérone (T). L'évaluation pharmacocinétique a été exécutée à l'aide du TOPFIT et les paramètres ont été évalués en vue de déterminer les différences avec les résultats du test-t. Les principales variables ciblées étaient lesC max,t max et ASC pour l'éthinyl oestradiol, GSD et GSD non lié, au jour 21 du cycle 3 par rapport au CPj21.

La pharmacocinétique de l'EE2 correspondait à une dose de 20 μg/unité. LeC max d'une dose unique de 65 pg/ml et l'ASC de 612 pg h ml−1 augmentaient de 40 à 60% durant les cycles de traitement par suite d'accumulation. L'EE2 induisait des taux sériques de SHBG de base (102 nmol/l) et de CBG (42 μg/ml) d'environ 220 nmol/l et 87 μl/ml respectivement à la fin des premier et troisième cycles.

Les taux sériques de T tombaient à 50% des niveaux de base durant les cycles de traitement et les concentrations de T libre étaient réduites de 60 à 70%. La pharmacocinétique du GSD à la fin des cycles de traitement 1 et 3 était différente de celle d'une dose unique. LesC max d'une dose unique de 3,5 ng/ml et l'ASC0–24h de 22 ng h ml−1 augmentaient jusqu'à des niveaux stables de δ-8,7 ng/ml et 90–106 ng h ml−1 respectivement. La hausse des taux de GSD durant le traitement résulte de deux processus parallèles: accumulation et élargissement du compartiment spécifiquement liant. Ce fait est démontré par des expériences de liaison des protéines, lesquelles indiquent une liaison spécifique accrue (SHBG), passant de 69 à 80% et une réduction de la fraction libre de GSD de 40% au cours du traitement.

Les résultats de la pharmacocinétique du GSD et de l'EE2 obtenus dans la présente étude confirment ceux obtenus précédemment avec le Femodene, lorsque la réduction de 10 μg/j de la dose de EE2 est prise en compte.

Resumen

Este estudio se realizó con 14 mujeres jóvenes. La combinación de anticonceptivos orales contenía 75 μg de gestodén (GDS) y 20 μg de etinil estradiol (EE2) por unidad de dosificación. Las voluntarias recibieron una sola dosis en el vigésimo primer día de un preciclo sin tratamiento (PCd21) y, después de un período de interrupción de siete días — utilizaron la preparación al séptimo día de un programa de 21 días durante tres meses. Se obtuvieron perfiles diarios del nivel sérico de los fármacos en el PCd21 y en los días 1 y 21 de los ciclos del primer y tercer ciclo de tratamiento. Además, se realizó el seguimiento de los niveles séricos mínimos de los fármacos cada dos días durante el primer y tercer ciclo de tratamiento. Los niveles séricos de GSD, EE2, CBG, SHBG y testosterona (T) se determinaron mediante RIA específicamente desarrollados o comercialmente disponibles. La evaluación farmacocinética se realizó con TOPFIT y se evaluaron las diferencias de los parámetros con el test-t. Las principales variables a determinar fueronC máx,t máx y AUC para EE2, GSD y GSD no ligado al vigésimo primer día del tercer ciclo en comparación con PCd21.

La farmacocinética de EE2 guardaba conformidad con una dosis de 20 μg/unidad. LaC máx de dosis única de 65 pg/ml y AUC de 612 pg h ml−1 aumentó en un 40–60% durante los ciclos de tratamiento debido a la acumulación. EE2 indujo niveles séricos de SHBG basal (102 nmol/l) y CBG (42 μg/ml) de aproximadamente 220 nmol/l y 87 μg/ml, respectivamente, al final del primer y tercer ciclo de tratamiento.

Los niveles séricos de T se redujeron al 50% de los niveles de línea de referencia durante los ciclos de tratamiento y las concentraciones de T libre se redujeron en un 60–70%. La farmacocinética del GSD al concluir el primer y tercer ciclo de tratamiento fue diferente de la correspondiente a la dosis única. LaC máx de dosis única de 3,5 ng/ml y AUC0–24h de 22 ng h ml−1 aumentó a niveles de estado estable de 8–8,7 ng/ml y 90–106 ng h ml−1, respectivamente. El aumento de los niveles de GSD con el tratamiento se debe a dos procesos paralelos, es decir, acumulación y ampliación del compartimiento específico de ligazón. Esto se demostró mediante experimentos de ligazón de proteínas, que señalaron un aumento de la ligazón específica (SHBG) del 69% al 80% y una reducción de la fracción libre de GSD en un 40% durante el tratamiento.

Los resultados de la farmacocinética de GSD y EE2 obtenidos en el presente estudio confirman resultados anteriores con Femodene, al tenerse en cuenta la reducción de la dosis de EE2 en 10 μg/d.

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References

  1. Elger W, Steinbeck H, Schillinger E, Losert W, Beier S. Endocrine-pharmacological profile of gestodene. Adv Control Deliv Syst. 1986;2:182–97.

    Google Scholar 

  2. Losert W, Casal-Stenzel J, Buse M. Progestogens with antimineralocorticoid activity. Drug Res. 1985;35:459–71.

    Google Scholar 

  3. Täuber U, Kuhnz W, Hümpel M. Pharmacokinetics of gestodene and ethinyl estradiol after oral administration of a monophasic contraceptive. Am J Obstet Gynecol. 1990;163:1414–20.

    PubMed  Google Scholar 

  4. Dibbelt L, Knuppen R, Kuhnz W, Jütting G. Pharmacokinetics and protein binding of gestodene under treatment with a low-dose combination oral contraceptive for three months. Drug Res. 1992;42:1146–52.

    Google Scholar 

  5. Kuhnz W, Baumann A, Staks T, Dibbelt L, Knuppen R, Jütting G.. Pharmacokinetics of gestodene and ethinylestradiol in 14 women during three months of treatment with a new tri-step combination oral contraceptive: Serum protein binding of gestodene and influence of treatment on free and total testosterone levels in the serum. Contraception. 1993;48:303–22.

    Article  PubMed  Google Scholar 

  6. Kuhnz W, Gansau C, Fuhrmeister A. Pharmacokinetics of gestodene in 12 women who received a single oral dose of 0.075 mg gestodene and, after a wash-out phase, the same dose during one treatment cycle. Contraception. 1992;46:29–40.

    Article  PubMed  Google Scholar 

  7. Orme M, Back DJ, Ward S, Green S. The pharmacokinetics of ethinylestradiol in the presence and absence of gestodene and desogestrel. Contraception. 1991;43:305–23.

    Article  PubMed  Google Scholar 

  8. Kuhnz W, Staks T, Jütting G. Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: Serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum. Contraception. 1994;50:563–79.

    Article  PubMed  Google Scholar 

  9. Kuhnz W, Staks T, Jütting G. Pharmacokinetics of cyproterone acetate and ethinylestradiol in 15 women who received a combination oral contraceptive during three treatment cycles. Contraception. 1993;48:557–75.

    Article  PubMed  Google Scholar 

  10. Kuhnz W, Hümpel M, Biere H, Gross D. Influence of repeated oral doses of ethinylestradiol on the total serum clearance of13C-ethinylestradiol in young women. [submitted for publication].

  11. Dibbelt L, Knuppen R, Jütting G, Heimann S, Klipping CO, Parikka-Olexik H. Group comparison of serum ethinyl estradiol, SHBG and CBG levels in 83 women using two low-dose combination oral contraceptives for three months. Contraception. 1990;43:1–21.

    Article  Google Scholar 

  12. Kuhnz W, Al-Yacoub G, Fuhrmeister A. Pharmacokinetics of levonorgestrel and ethinylestradiol in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation. Contraception. 1992;46:455–69.

    Article  PubMed  Google Scholar 

  13. Hümpel M, Täuber U, Kuhnz W et al., Protein binding of active ingredients and comparison of serum ethinyl estradiol, sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels in women using a combination of gestodene/ethinyl estradiol (Femovan) or a combination of desogestrel/ethinyl estradiol (Marvelon) and single dose ethinyl estradiol bioequivalence from both oral contraceptives. Am J Obstet Gynecol. 1990;163:329–33.

    PubMed  Google Scholar 

  14. Kuhnz W, Louton T, Back DJ, Michaelis K. Radioimmunological analysis of ethinylestradiol in human serum. Validation of the method and comparison with a gas chromatographic/mass spectrometric assay. Drug Res. 1993;43:16–21.

    Google Scholar 

  15. Nieuweboer B, Tack J, Hümpel M, Täuber U. Development and application of a radioimmunoassay of the new progestogen gestagene. Contraception. 1989;40:313–23.

    Article  PubMed  Google Scholar 

  16. Heinzel G, Woloszczak R, Thomann P. TOPFIT 2.0 Pharmacokinetic and pharmacodynamic data analysis system for the PC. Stuttgart, Jena, New York: Gustav Fischer; 1993.

    Google Scholar 

  17. Schwartz U, Hammerstein J. The oestrogenic potency of various contraceptive steroids as determined by their effects on transcortin-binding capacity. Acta Endocrinol. 1974;76:156–71.

    Google Scholar 

  18. Hammerstein J, Daume E, Simon A et al. Influence of gestodene and desogestrel as components of low-dose oral contraceptives on the pharmacokinetics of ethinyl estradiol (EE2), on serum CBG and on urinary cortisol and 6β-hydroxycortisol. Contraception. 1993;47:263–81.

    Article  PubMed  Google Scholar 

  19. Jung-Hoffmann C, Heidt F, Kuhl H. Effect of two oral contraceptives containing 30 μg ethinylestradiol and 75 μg gestodene or 150 μg desogestrel upon various hormonal parameters. Contraception. 1988;38:593–603.

    Article  PubMed  Google Scholar 

  20. Zamah NM, Hümpel M, Kuhnz W, Louton T, Rafferty J, Back DJ. Absence of an effect of high vitamin C dosage on the systemic availablity of ethinyl estradiol in women using a combination oral contraceptive. Contraception. 1993;48:377–91.

    Article  PubMed  Google Scholar 

  21. Zuo M, Karras D, Hümpel M. Influence of protein binding on the metabolic clearance rate of synthetic progestins in the rat liver perfusion model. Drug Res. 1992;42:1130–8.

    Google Scholar 

  22. Fitzgerald C, Feichtinger W, Spona J et al. A comparison of the effects of two monophasic low dose oral contraceptives on the inhibition of ovulation. Adv Contracept. 1994;10:5–18.

    PubMed  Google Scholar 

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Heuner, A., Kuhnz, W., Heger-Mahn, D. et al. A single-dose and 3-month clinical—pharmacokinetic study with a new combination oral contraceptive. Adv Contracept 11, 207–225 (1995). https://doi.org/10.1007/BF01978421

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