Advertisement

Vaginal ring delivery of selective progesterone receptor modulators for contraception

      Abstract

      Vaginal ring delivery of selective progesterone receptor modulators (SPRMs) is under development to address the limitations of current hormonal methods that affect use and effectiveness. This method would be appropriate for use in women with contraindications to, or preferences to avoid, estrogens. A contraceptive vaginal ring (CVR) also eliminates the need for daily dosing and therefore might improve the effectiveness of contraception. The principal contraceptive effect of SPRMs is the suppression of ovulation. One limiting factor of chronic SPRM administration is the development of benign endometrial thickening characterized as PRM-associated endometrial changes. Ulipristal acetate (UPA) is approved for use as an emergency contraceptive pill, but no SPRM is approved for regular contraception. The Population Council is developing an ulipristal acetate CVR for regular contraception. The CVR studied is of a matrix design composed of micronized UPA mixed in a silicone rubber matrix The target product is a ring designed for continuous use over 3 months delivering near steady-state drug levels that will suppress ovulation. Results from Phase 1 and 2 studies demonstrate that suppression of ovulation occurs with UPA levels above 6–7 ng/mL.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Contraception
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Finer L.B.
        • Zolna M.R.
        Unintended pregnancy in the United States: incidence and disparities, 2006.
        Contraception. 2011; 84: 478-485
        • Trussell J.
        Contraceptive failure in the United States.
        Contraception. 2011; 83: 397-404
        • Curtis K.M.
        • Jamieson D.J.
        • Peterson H.B.
        • Marchbanks P.A.
        Adaptation of the World Health Organization's medical eligibility criteria for contraceptive use for use in the United States.
        Contraception. 2010; 82: 3-9
        • Dieben T.O.
        • Roumen F.J.
        • Apter D.
        Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring.
        Obstet Gynecol. 2002; 100: 585-593
        • Clinical Study report
        Protocol 300A/B. Population Council, New York, NY2012 ([data on file].)
        • Massai R.
        • Diaz S.
        • Jackanicz T.
        • Croxatto H.B.
        Vaginal rings for contraception in lactating women.
        Steroids. 2000; 65: 703-707
        • Edelman A.
        • Lew R.
        • Cwiak C.
        • Nichols M.
        • Jensen J.
        Acceptability of contraceptive-induced amenorrhea in a racially diverse group of US women.
        Contraception. 2007; 75: 450-453
        • Gainer E.E.
        • Ulmann A.
        Pharmacologic properties of CDB(VA)-2914.
        Steroids. 2003; 68: 1005-1011
        • Attardi B.J.
        • Burgenson J.
        • Hild S.A.
        • Reel J.R.
        In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone.
        J Steroid Biochem Mol Bio. 2004; 88: 277-288
        • Larner J.M.
        • Reel J.R.
        • Blye R.P.
        Circulating concentrations of the antiprogestins CDB-2914 and mifepristone in the female rhesus monkey following various routes of administration.
        Hum Reprod. 2000; 15: 1100-1106
        • Stratton P.
        • Hartog B.
        • Hajizadeh N.
        • et al.
        A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women.
        Hum Reprod. 2000; 15: 1092-1099
        • Brache V.
        • Cochon L.
        • Jesam C.
        • et al.
        Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.
        Hum Reprod. 2010; 25: 2256-2263
        • Glasier A.F.
        • Cameron S.T.
        • Fine P.M.
        • et al.
        Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
        Lancet. 2010; 375: 555-562
        • Chabbert-Buffet N.
        • Pintiaux-Kairis A.
        • Bouchard P.
        Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial.
        JCEM. 2007; 92: 3582-3589
        • Lakha F.
        • Ho P.C.
        • Van der Spuy Z.M.
        • et al.
        A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
        Hum Reprod. 2007; 22: 2428-2436
        • Bertagna X.
        • Escourolle H.
        • Pinquier J.L.
        • et al.
        Administration of RU 486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral cortisol deprivation.
        J Clin Endocrinol Metab. 1994; 78: 375-380
        • Spitz I.M.
        • Grunberg S.M.
        • Chabbert-Buffet N.
        • Lindenberg T.
        • Gelber H.
        • Sitruk-Ware R.
        Management of patients receiving long-term treatment with mifepristone.
        Fertil Steril. 2005; 84: 1719-1726
        • Brenner R.M.
        • Slayden O.D.
        Progesterone receptor antagonists and the endometrial antiproliferative effect.
        Semin Reprod Med. 2005; 23: 74-81
        • Brenner R.M.
        • Slayden O.D.
        • Nath A.
        • Tsong Y.Y.
        • Sitruk-Ware R.
        Intrauterine administration of CDB-2914 (ulipristal) suppresses the endometrium of rhesus macaques.
        Contraception. 2010; 81: 336-342
        • Croxatto H.B.
        • Brache V.
        • Sitruk-Ware R.
        • Kumar N.
        • Sivin I.
        A study to evaluate the effect of a contraceptive vaginal ring delivering a daily dose of 400–500 μg of CDB-2914 on pharmacokinetics and pharmacodynamics in normal cycling women. Summary study report. Protocol 312. Population Council, New York, NY2003 ([data on file])
        • Brache V.
        • Sitruk-Ware R.
        • Williams A.
        • et al.
        Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women.
        Contraception. 2012; 85: 480-488
        • Hoogland H.J.
        • Skouby S.O.
        Ultrasound evaluation of ovarian activity under oral contraceptives.
        Contraception. 1993; 47: 583-590
        • Mutter G.L.
        • Bergeron C.
        • Deligdisch L.
        • et al.
        The spectrum of endometrial pathology induced by progesterone receptor modulators.
        Mod Pathol. 2008; 21: 591-598