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 [AUC_0–12 _h]).

Results

First dose pharmacokinetics were obtained in HIV-negative premenopausal women and HIV-infected post-menopausal 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 pre-menopausal 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 (9,725– 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 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.

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