Original research article| Volume 85, ISSUE 6, P595-601, June 2012

Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial



      This study evaluated the ethinyl estradiol (EE) and levonorgestrel (LNG) pharmacokinetic profiles of AG200-15, a transdermal contraceptive delivery system, compared with a combination oral contraceptive (COC) containing EE 35 mcg and norgestimate 250 mcg.

      Study design

      A Phase 1, open-label, single-center study in 36 healthy women was conducted over three cycles with a randomized crossover design. After a run-in cycle of 21 days on and 7 days off with AG200-15, participants were randomized to receive one of two treatments: a 21/7-day cycle of AG200-15 either followed or preceded by one cycle of the COC. This trial is registered on under the identifier NCT01243580.


      During the third week of AG200-15 use, mean (��standard deviation) maximum serum concentration (Cmax), area under the curve0���168 h and steady-state concentration (Css48���168 h) for EE were 51.3��17.3 pg/mL, 6.26��2.46 ng h/mL and 35.7��14.5 pg/mL, respectively; for LNG, the corresponding values were 2400��1140 pg/mL, 317��159 ng h/mL and 1847��930 pg/mL, respectively. The AG200-15 EE Cmax was approximately 60% lower and the EE Css was 15%���20% lower than those obtained with the COC. The calculated daily dose of AG200-15 was equivalent to a 30-mcg EE COC. The most common adverse events (AEs; >10%) in the AG200-15 group were headache, nausea and application-site irritation. All drug-related AEs were mild, and no serious AEs were reported.


      EE and LNG daily exposure during AG200-15 treatment was within the range reported for a low-dose COC. The daily EE dose with AG 200-15 was equivalent to a 30-mcg COC and was safe and well tolerated.


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


        • Archer D.F.
        • Cullins V.
        • Creasy G.W.
        • Fisher A.C.
        The impact of improved compliance with a weekly contraceptive transdermal system (Ortho Evra) on contraceptive efficacy.
        Contraception. 2004; 69: 189-195
        • Archer D.F.
        • Bigrigg A.
        • Smallwood G.H.
        • Shangold G.A.
        • Creasy G.W.
        • Fisher A.C.
        Assessment of compliance with a weekly contraceptive patch (Ortho Evra/Evra) among North American women.
        Fertil Steril. 2002; 77: S27-S31
        • Urdl W.
        • Apter D.
        • Alperstein A.
        • et al.
        Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception.
        Eur J Obstet Gynecol Reprod Biol. 2005; 121: 202-210
        • van den Heuvel M.W.
        • van Bragt A.J.M.
        • Alnabawy A.K.M.
        • Kaptein M.C.J.
        Comparison of ethinyl estradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive.
        Contraception. 2005; 72: 168-174
        • Devineni D.
        • Skee D.
        • Vaccaro N.
        • et al.
        Pharmacokinetics and pharmacodynamics of a transdermal contraceptive patch and an oral contraceptive.
        J Clin Pharmacol. 2007; 47: 497-509
      1. Ortho Evra�� [package insert]. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2008.

        • Cole J.A.
        • Norman H.
        • Doherty M.
        • Walker A.M.
        Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users.
        Obstet Gynecol. 2007; 109: 339-346
        • Stanczyk F.Z.
        • Rubin A.
        • Flood L.
        • Foegh M.
        Pharmacokinetics, tolerability and cycle control of three transdermal contraceptive delivery systems containing different doses of ethinyl estradiol and levonorgestrel.
        Horm Mol Biol Clin Investig. 2011; 6: 231-240
        • Abrams L.S.
        • Skee D.M.
        • Wong F.A.
        • Anderson N.J.
        • Leese P.T.
        Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches.
        J Clin Pharmacol. 2001; 41: 1232-1237
        • Licea-Perez H.
        • Wang S.
        • Bowen C.L.
        • Yang E.
        A semi-automated 96-well plate method for the simultaneous determination of oral contraceptives concentrations in human plasma using ultra performance liquid chromatography coupled with tandem mass spectrometry.
        J Chromatogr B Analyt Technol Biomed Life Sci. 2007; 852: 69-76
        • Spona J.
        • Feichtinger W.
        • Kindermann C.
        • W��nsch C.
        • Brill K.
        Inhibition of ovulation by an oral contraceptive containing 100 micrograms levonorgestrel in combination with 20 micrograms ethinylestradiol.
        Contraception. 1996; 54: 299-304
      2. Seasonique�� NDA. Available at: Retrieved November 30, 2010.

      3. Levlite�� NDA. Available at: Retrieved November 30, 2010.

        • Endrikat J.
        • Blode H.
        • Gerlinger C.
        • Rosenbaum P.
        • Kuhnz W.
        A pharmacokinetic study with a low-dose oral contraceptive containing 20 microg ethinylestradiol plus 100 microg levonorgestrel.
        Eur J Contracept Reprod Health Care. 2002; 7: 79-90
        • Blode H.
        • Wuttke W.
        • Loock W.
        • R��ll G.
        • Heithecker R.
        A 1-year pharmacokinetic investigation of a novel oral contraceptive containing drospirenone in healthy female volunteers.
        Eur J Contracept Reprod Health Care. 2000; 5: 256-264
        • 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: 455-469