Advertisement
Original research article| Volume 75, ISSUE 6, P454-460, June 2007

Pharmacokinetic study to compare the absorption and tolerability of two doses of levonorgestrel following single vaginal administration of levonorgestrel in Carraguard�� gel: a new formulation for ���dual protection��� contraception

      Abstract

      Objective

      The study was conducted to assess levonorgestrel (LNG) serum levels achieved after a single administration of two different doses of Carraguard vaginal gel containing LNG (CARRA/LNG), designed for use as microbicide and contraceptive for potential dual protection.

      Materials and Methods

      This was a randomized double-blind pharmacokinetic study conducted in 12 subjects enrolled at two centers. Each subject received a single vaginal administration of CARRA/LNG containing either 0.75 or 1.5 mg LNG per 4 mL of gel on Days 10���12 of the menstrual cycle. LNG serum levels were measured at 0, 1, 2, 4, 8 and 12 h after administration and for the following 7 days. LH and progesterone (for a preliminary evaluation of effect on the ovarian function) as well as SHBG were measured in the daily samples.

      Results

      Serum LNG maximum concentrations (Cmax) were 14.1��2.1 and 11.7��2.7 nmol/L and Tmax was 12.0 and 6.0 h for the low and high dose, respectively, with large intersubject variability within the first 48 h. Mean levels at 96 h were 10% of Cmax. Differences in AUC between both doses were not statistically significant. SHBG levels decreased approximately 25% by Day 4 after administration. Luteal activity was observed in 3/6 and 5/6 of the subjects in the low- and high-dose group, respectively.

      Conclusion

      This study demonstrates that the CARRA/LNG gel can sustain elevated serum levels of the contraceptive steroid for up to 96 h after a single application. The serum levels attained with the 0.75-mg formulation are in the range expected to perturb the ovulatory process as observed in some subjects. The lack of correlation between the administered dose and serum concentrations of the steroid may be related to a rate-limiting absorption of LNG from the vaginal mucosa. The results reported here suggest that the CARRA/LNG formulation has good potential to become a dual-protection method, possibly preventing conception and sexually transmitted infections.

      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

        • Baba M.
        • Nakajima M.
        • Schols D.
        • Pauwels R.
        • Balzarini J.
        • De Clercq E.
        Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro.
        Antiviral Res. 1988; 9: 335-343
        • Pearce-Pratt R.
        • Phillips D.M.
        Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of HIV-1.
        Biol Reprod. 1996; 54: 173-182
        • Zacharopoulos V.R.
        • Phillips D.M.
        Vaginal formulations of carrageenan protect mice from herpes simplex virus infection.
        Clin Diagn Lab Immunol. 1997; 4: 465-468
        • Jerse A.E.
        Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice.
        Infect Immun. 1999; 67: 5699-5708
        • Maguire R.
        • Bergman N.
        • Phillips D.M.
        Comparison of microbicides for efficacy in protecting mice against vaginal challenge with herpes simplex virus type 2, cytoxicity, antibacterial properties, and sperm immobilization.
        Sex Transm Dis. 2001; 28: 259-265
        • Elias C.J.
        • Coggins C.
        • Alvarez F.
        • et al.
        Colposcopic evaluation of a vaginal gel formulation of iota-carrageenan.
        Contraception. 1997; 56: 387-389
        • Coggins C.
        • Blanchard K.
        • Alvarez F.
        • et al.
        Preliminary safety and acceptability of a carrageenan gel for possible use as a vaginal microbicide.
        Sex Transm Inf. 2000; 76: 480-483
        • Mishell D.J.
        • Lumkin M.
        • Jackanicz T.
        Initial clinical studies of intravaginal rings containing norethindrone and norgestrel.
        Contraception. 1975; 12: 253-260
        • Victor A.
        • Johansson E.
        Plasma levels of d-norgestrel and ovarian function in women using intravaginal rings impregnated with d-norgestrel for several cycles.
        Contraception. 1976; 14: 215-226
        • Sivin I.
        • Mishell D.R.
        • Victor A.
        • et al.
        A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. I ��� Use effectiveness. An international comparative trial.
        Contraception. 1981; 24: 341-358
        • Landgren B.M.
        • Aedo A.R.
        • Johannisson E.
        • Cekan S.Z.
        Pharmacokinetic and pharmacodynamic effects of vaginal rings releasing levonorgestrel at a rate of 27 micrograms/24 hs: a pilot study.
        Contraception. 1994; 49: 139-150
        • World Health Organization
        Microdose intravaginal levonorgestrel contraception: a multicenter clinical trial: I. Contraceptive efficacy and side effects.
        Contraception. 1990; 41: 105-124
        • Alvarez-Sanchez F.
        • Brache V.
        • Jackanicz T.
        • Faundes A.
        Evaluation of four different contraceptive vaginal rings: steroid serum levels, luteal activity, bleeding control and lipid profiles.
        Contraception. 1992; 46: 387-397
        • Ballagh S.
        • Mishell D.R.
        • Jackanicz T.
        • Lacarra M.
        • Eggena P.
        Dose-finding study of a contraceptive ring releasing norethindrone acetate/ethinyl estradiol.
        Contraception. 1994; 50: 535-549
        • Stanczyk F.Z.
        • Hiroi M.
        • Goebelsmann U.
        • Brenner P.F.
        • Lumkin M.E.
        • Mishell D.R.
        Radioimmunoassay of serum d-norgestrel in women following oral and intravaginal administration.
        Contraception. 1975; 12: 279-298
        • Brache V.
        • Blumenthal P.
        • Alvarez F.
        • Dunson T.
        • Cochon L.
        • Faundes A.
        Timing of onset of contraceptive effectiveness in Norplant implant users: II. Effect on the ovarian function in the first cycle of use.
        Contraception. 1999; 59: 245-251
        • Von Hertzen H.
        • Piaggio G.
        • Ding J.
        • et al.
        World Health Organization. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.
        Lancet. 2002; 360: 1803-1810
        • World Health Organization and CONRAD
        Manual for the standardization for the evaluation of vaginal products.
        WHO and CONRAD, Geneva and Arlington2004 (WHO/RHR/04.02 and CONRAD/2004.1)
        • Jick H.
        • Hannan M.T.
        • Stergachis A.
        • Heidrich F.
        • Perera D.R.
        • Rothman K.J.
        Vaginal spermicides and gonorrhea.
        JAMA. 1982; 248: 1619-1621
        • Hicks D.R.
        • Martin L.S.
        • Getchell J.P.
        • et al.
        Inactivation of HTLV III/LAV infected cultures of normal human lymphocytes by nonoxynol-9 in vitro.
        Lancet. 1985; 2: 1422-1423
        • Louv W.C.
        • Austin H.
        • Alexander W.J.
        • Stagno S.
        • Cheeks J.
        A clinical trial of nonoxynol-9 for preventing gonococcal and chlamydial infections.
        J Infect Dis. 1988; 158: 518-523
        • Mauck C.K.
        • Baker J.M.
        • Barr S.P.
        • Abercrombie T.J.
        • Archer D.F.
        A phase I comparative study of contraceptive vaginal films containing benzalkonium chloride and nonoxynol-9. Postcoital testing and colposcopy.
        Contraception. 1997; 56: 89-96
        • Roddy R.E.
        • Zekeng L.
        • Ryan K.A.
        • Tamoufe U.
        • Weir S.S.
        • Wong E.L.
        A controlled trial of nonoxynol-9 film to reduce male to female transmission of sexual transmitted disease.
        N Engl J Med. 1998; 339: 504-510
        • Bourinbaiar A.S.
        • Lee-Huang S.
        Comparative in vitro study of contraceptive agents with anti-HIV activity: gramicidin, nonoxynol-9, gossypol.
        Contraception. 1994; 49: 131-137
        • Van Damme L.
        • Ramjee G.
        • Alary M.
        • et al.
        Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomized controlled trial.
        Lancet. 2002; 360: 971-977
        • D'Cruz O.J.
        • Uckun F.M.
        Clinical development of microbicides for the prevention of HIV infection.
        Curr Pharm Des. 2004; 10: 315-336
        • Smita J.
        • Soma D.
        • Beverly B.
        • et al.
        Phase I safety study of 0.5% PRO 2000 vaginal gel among HIV un-infected women in Pune, India.
        AIDS Res Ther. 2006; 3: 4
        • Van Damme L.
        • Wright A.
        • Depraetere K.
        • et al.
        A phase I study of a novel potential intravaginal microbicide, PRO 2000, in healthy sexually inactive women.
        Sex Transm Infect. 2000; 76: 126-130
        • Van De Wijgert J.
        • Fullem A.
        • Kelly C.
        • et al.
        Phase 1 trial of the topical microbicide BufferGel: safety results from four international sites.
        J Acquir Immune Defic Syndr. 2001; 26: 21-27
        • Malonza I.M.
        • Mirembe F.
        • Nakabiito C.
        • et al.
        Expanded Phase I safety and acceptability study of 6% cellulose sulfate vaginal gel.
        AIDS. 2005; 19: 2157-2163
        • Johansson E.
        • Brache V.
        • Alvarez F.
        • et al.
        Pharmacokinetic study of different dosing regimens of levonorgestrel for emergency contraception in healthy women.
        Hum Reprod. 2002; 17: 1472-1476
        • Tremblay D.
        • Gainer E.
        • Ulmann A.
        The pharmacokinetics of 750 ��g levonorgestrel after administration of one single dose or two doses at 12- or 24-h interval.
        Contraception. 2002; 64: 327-331
        • Kook K.
        • Gabelnick H.
        • Duncan G.
        Pharmacokinetics of levonorgestrel 0.75 mg tablets.
        Contraception. 2002; 66: 73-76
        • Kives S.
        • Hahn P.
        • White E.
        • Stanczyk F.Z.
        • Reid R.
        Bioavailability of the Yuzpe and levonorgestrel regimens of emergency contraception: vaginal vs. oral administration.
        Contraception. 2005; 71: 197-201
        • Devoto L.
        • Fuentes A.
        • Palomino A.
        • et al.
        Pharmacokinetics and endometrial tissue levels of levonorgestrel after administration of a single 1.5-mg dose by the oral and vaginal route.
        Fertil Steril. 2005; 84: 46-51
        • Alvarez F.
        • Faundes A.
        • Johansson E.
        • Coutinho E.
        Blood levels of levonorgestrel in women following vaginal placement of contraceptive pills.
        Fertil Steril. 1983; 40: 120-123
        • Timmer C.J.
        • Mulders T.M.
        Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring.
        Clin Pharmacokinet. 2000; 39: 233-242
        • Alexander N.J.
        • Baker E.
        • Kaptein M.
        • Karck U.
        • Miller L.
        • Zampaglione E.
        Why consider vaginal drug administration?.
        Fertil Steril. 2004; 82: 1-12
        • Croxatto H.B.
        • Brache V.
        • Pavez M.
        • et al.
        Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75 mg dose given on the days preceding ovulation.
        Contraception. 2004; 70: 442-450
        • Kesseru E.
        • Lanrranaga A.
        • Parada J.
        Postcoital contraception with d-norgestrel.
        Contraception. 1973; 7: 367-379
        • Kesseru E.
        • Garmedndia F.
        • Westphal N.
        • Parada J.
        The hormonal and peripheral effects of d-norgestrel in postcoital contraception.
        Contraception. 1974; 10: 411-423
        • Brache V.
        • Faundes A.
        • Johansson E.
        • Alvarez F.
        Anovulation, inadequate luteal phase and poor sperm penetration in cervical mucus during prolonged use of Norplant implants.
        Contraception. 1985; 31: 261-273
        • Croxatto H.B.
        • Diaz S.
        • Salvatierra A.M.
        • Morales P.
        • Ebensperger C.
        • Brandeis A.
        Treatment with Norplant subdermal implants inhibits sperm penetration through cervical mucus in vitro.
        Contraception. 1987; 36: 193-201
        • Dunson T.R.
        • Blumenthal P.D.
        • Alvarez F.
        • et al.
        Timing of onset of contraceptive effectiveness in Norplant implant users: Part I. Changes in cervical mucus.
        Fertil Steril. 1998; 69: 258-266