title: Effect of HIV infection and menopause status on raltegravir pharmacokinetics in the blood and genital tract.
abstract: BACKGROUND
  This study describes first dose and steady state pharmacokinetics of raltegravir (RAL) in cervicovaginal fluid (CVF) and blood plasma (BP).
  
  
  METHODS
  Three cohorts of women were enrolled sequentially in a single-site, open-label pharmacokinetic study of oral raltegravir 400 mg twice daily: HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women. BP and CVF were collected over 12 h after a single observed dose and at steady state. RAL concentrations were measured by HPLC-MS methods. Data are expressed as median (IQR). The ANOVA rank-sum test was used to evaluate between-group differences in steady state raltegravir exposure (area under the concentration-time curve over the 12-h dosing interval [AUC0-12 h]).
  
  
  RESULTS
  First dose pharmacokinetics were obtained in HIV-negative premenopausal women and HIV-infected post-menopausal women only. The median (IQR) BP AUC0-12 h was 3,099 (985-5,959) and 4,239 (2,781-13,695) ng•h/ml and the median (IQR) CVF AUC0-12 h was 1,720 (305-5,288) and 13,797 (11,066-19,563) ng•h/ml for HIV-negative premenopausal and HIV-infected post-menopausal women, respectively. All cohorts contributed to steady-state pharmacokinetic profiles. Median (IQR) BP AUC0-12 h did not differ between the groups: 8,436 (3,080-10,111), 5,761 (1,801-10,095) and 6,180 (5,295-8,282) ng•h/ml in HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women, respectively. There was a trend for lower CVF AUC0-12 h among HIV-negative women 3,164 (1,156-9,540) compared to 11,465 (9,725-17,138) and 9,568 (4,271-24,306) ng•h/ml HIV-infected premenopausal and HIV-infected post-menopausal women, respectively, but this was not statistically significant (P=0.08). HIV-negative premenopausal women had a median (IQR) CVF:BP AUC0-12 h ratio of 0.46 (0.2-1.1), whereas HIV-infected premenopausal and post-menopausal women had median (IQR) CVF:BP AUC0-12 h ratio of 3.9 (1.2-6.7) and 1.4 (0.7-4.3), respectively.
  
  
  CONCLUSIONS
  This is the first study to investigate RAL exposure in BP and CVF in premenopausal HIV-negative and pre- and post-menopausal HIV-infected women. These data indicate HIV and menopausal status may influence antiretroviral distribution into the female genital tract.
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Mackenzie L
authors.initials: ML
authors.lastname: Cottrell
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.forename: Heather M A
authors.initials: HM
authors.lastname: Prince
authors.forename: Amanda
authors.initials: A
authors.lastname: Jones
authors.forename: Nicole
authors.initials: N
authors.lastname: White
authors.forename: Ruili
authors.initials: R
authors.lastname: Wang
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015331:Cohort Studies; D005260:Female; D005836:Genitalia, Female / Q000378:metabolism* / Q000821:virology; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000068898:Raltegravir Potassium