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 day 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 seven 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 (C max ) were 14.1 ± 5.1 and 11.7 ± 6.5 nmol/L and T max 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 C max . 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 dualprotection method, possibly preventing conception and sexually transmitted infections.

Effect of mifepristone on endometrial matrix metalloproteinase expression and leukocyte abundance in new medroxyprogesterone acetate users

“…One of the possible uses of this gel would be a pre-coital emergency contraceptive, for application before occasional intercourse. A recent pharmacokinetic study with CARRA/LNG containing 1.5 or 0.75 mg of levonorgestrel in 4 mL of gel, confirmed the vaginal absorption of this steroid [10]. LNG serum levels in the range known to interfere with the ovulatory process were achieved, thereby confirming the potential of CARRA/LNG gel as a new candidate product that could provide dual protection, both for prevention of pregnancy as well as prevention of STI.…”

“…Mean serum LNG levels on days 1-5 after treatment with the single oral 0.75 mg dose in the Croxatto et al study [12] were between 30 and 60% higher than those observed in the present study after administration of the same dose via CARRA/LNG gel. Furthermore, pharmacokinetic studies indicate that the high peak that occurs 1-2 h after oral administration is missing after the administration of the vaginal gel [10,[14][15][16]. A lower Cmax and a later Tmax have similarly been reported with the vaginal route as compared with oral route of administration of LNG emergency contraceptive pills [17][18][19].…”

Effect of sexual intercourse on the absorption of levonorgestrel after vaginal administration of 0.75 mg in Carraguard® gel: a randomized, cross-over, pharmacokinetic study

“…Maximum serum levels between 3.5 and 22.01 nmol/L were attained at 4–12 h following application confirming the vaginal absorption of this steroid [12]. …”

Emerging female contraceptives

“…The ingredient is the carrageenan, PDR98 --15, which belongs to the sulfated polysaccharide class of compounds and has been shown to have in vitro antiviral and antibacterial properties against HIV, herpes simplex virus type 2 and Neisseria gonorrhoeae [70][71][72][73]. CARRA was tested to assess the use as a vehicle for the vaginal delivery of LNG with the dual purpose of preventing pregnancy and sexually transmitted infections.…”

“…In one study [71] conducted with 12 women, two CAR-RA--LNG gel formulations containing either 0.75 or 1.5 mg of LNG/4 ml of gel were evaluated and compared with respect to LNG absorption and clearance rates. Each woman used a single vaginal administration of CARRA--LNG containing one of the two doses on days 10 --12 of the menstrual cycle.…”