Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol

Pharmacokinetics from a dose-finding study

J. T. Jensen, A. B. Edelman, B. A. Chen, D. F. Archer, K. T. Barnhart, M. A. Thomas, Anne Burke, C. L. Westhoff, L. S. Wan, R. Sitruk-Ware, N. Kumar, B. Variano, D. L. Blithe

Research output: Contribution to journalArticle

Abstract

Background: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses. Study design: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. Results: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (C max) 918 pg/mL; time to maximum concentration (T max) 3.5 h. For E2, the C max occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. Conclusion: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. Implications: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.

Original languageEnglish (US)
JournalContraception
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Female Contraceptive Devices
Contraceptive Agents
Estradiol
Pharmacokinetics
Area Under Curve
ST 1435
Acetates
Bone and Bones

Keywords

  • Continuous cycling
  • Contraception
  • Contraceptive vaginal ring
  • Estradiol
  • Nestorone
  • Pharmacokinetics

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Jensen, J. T., Edelman, A. B., Chen, B. A., Archer, D. F., Barnhart, K. T., Thomas, M. A., ... Blithe, D. L. (Accepted/In press). Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: Pharmacokinetics from a dose-finding study. Contraception. https://doi.org/10.1016/j.contraception.2018.01.012

Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol : Pharmacokinetics from a dose-finding study. / Jensen, J. T.; Edelman, A. B.; Chen, B. A.; Archer, D. F.; Barnhart, K. T.; Thomas, M. A.; Burke, Anne; Westhoff, C. L.; Wan, L. S.; Sitruk-Ware, R.; Kumar, N.; Variano, B.; Blithe, D. L.

In: Contraception, 01.01.2018.

Research output: Contribution to journalArticle

Jensen, JT, Edelman, AB, Chen, BA, Archer, DF, Barnhart, KT, Thomas, MA, Burke, A, Westhoff, CL, Wan, LS, Sitruk-Ware, R, Kumar, N, Variano, B & Blithe, DL 2018, 'Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: Pharmacokinetics from a dose-finding study', Contraception. https://doi.org/10.1016/j.contraception.2018.01.012
Jensen, J. T. ; Edelman, A. B. ; Chen, B. A. ; Archer, D. F. ; Barnhart, K. T. ; Thomas, M. A. ; Burke, Anne ; Westhoff, C. L. ; Wan, L. S. ; Sitruk-Ware, R. ; Kumar, N. ; Variano, B. ; Blithe, D. L. / Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol : Pharmacokinetics from a dose-finding study. In: Contraception. 2018.
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abstract = "Background: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone{\circledR} (NES)) combined with one of three different estradiol (E2) doses. Study design: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. Results: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (C max) 918 pg/mL; time to maximum concentration (T max) 3.5 h. For E2, the C max occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. Conclusion: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. Implications: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.",
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T2 - Pharmacokinetics from a dose-finding study

AU - Jensen, J. T.

AU - Edelman, A. B.

AU - Chen, B. A.

AU - Archer, D. F.

AU - Barnhart, K. T.

AU - Thomas, M. A.

AU - Burke, Anne

AU - Westhoff, C. L.

AU - Wan, L. S.

AU - Sitruk-Ware, R.

AU - Kumar, N.

AU - Variano, B.

AU - Blithe, D. L.

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N2 - Background: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses. Study design: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. Results: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (C max) 918 pg/mL; time to maximum concentration (T max) 3.5 h. For E2, the C max occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. Conclusion: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. Implications: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.

AB - Background: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses. Study design: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. Results: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (C max) 918 pg/mL; time to maximum concentration (T max) 3.5 h. For E2, the C max occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. Conclusion: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. Implications: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.

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KW - Contraception

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