Effect of HIV Infection and Menopause Status on Raltegravir Pharmacokinetics in the Blood and Genital Tract. Issue 8 (November 2015)

• Record Type: Journal Article
• Authors: Cottrell, Mackenzie L; Patterson, Kristine B; Prince, Heather MA; Jones, Amanda; White, Nicole; Wang, Ruili; Kashuba, Angela DM
• Is Part Of: Antiviral therapy. Volume 20:Issue 8(2015)
• Page Start: 795
• Page End: 803
• Publication Date: 2015-11
• Subjects: Antiviral agents -- Periodicals; Antiviral Agents -- therapeutic use; Virus Diseases -- therapy; Viruses -- drug effects; Antiviral agents; Periodical; Electronic journals; Periodicals; 616.9106
• DOI: 10.3851/IMP2968
• Languages: English
• ISSNs: 1359-6535

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) ngh/ml and the median (IQR) CVF AUC0–12 h was 1, 720 (305–5, 288) and 13, 797 (11, 066–19, 563) ngh/ml for HIV-negative pre-menopausal 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) ngh/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) ngh/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.