Effect of HIV infection and menopause status on raltegravir pharmacokinetics in the blood and genital tract

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 [AUC(0-12 h)]). Results: First dose pharmacokinetics were obtained in HIV-negative premenopausal women and HIV-infected postmenopausal women only. The median (IQR) BP AUC(0-12 h) was 3,099 (985-5,959) and 4,239 (2,781-13,695) ng.h/ml and the median (IQR) CVF AUC(0-12 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 AUC(0-12 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 AUC(0-12 h) among HIV-negative women 3,164 (1,156-9,540) compared to 11,465 (9,72517,138) 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 AUC(0-12 h) ratio of 0.46 (0.2-1.1), whereas HIV-infected premenopausal and post-menopausal women had median (IQR) CVF: BP AUC(0-12 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.