title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Population Council, Center for Biomedical Research, New York, NY 10021, USA. regine@popcbr.rockefeller.edu
authors.forename: Regine
authors.initials: R
authors.lastname: Sitruk-Ware
authors.forename: Vivian
authors.initials: V
authors.lastname: Brache
authors.forename: Robin
authors.initials: R
authors.lastname: Maguire
authors.forename: Horacio
authors.initials: H
authors.lastname: Croxatto
authors.forename: Narender
authors.initials: N
authors.lastname: Kumar
authors.forename: Sushma
authors.initials: S
authors.lastname: Kumar
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Salvatierra
authors.forename: David
authors.initials: D
authors.lastname: Phillips
authors.forename: Anibal
authors.initials: A
authors.lastname: Faundes
mesh_terms: D000282:Administration, Intravaginal; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002677:Chile; D003283:Contraceptives, Postcoital, Synthetic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004293:Dominican Republic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D016912:Levonorgestrel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014622:Vaginal Creams, Foams, and Jellies
chemical_list: D000890:Anti-Infective Agents; D003283:Contraceptives, Postcoital, Synthetic; D014622:Vaginal Creams, Foams, and Jellies; D016912:Levonorgestrel