Dataset Information

Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing.

ABSTRACT: OBJECTIVES:To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men. DESIGN:A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days. METHODS:Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3. RESULTS:BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ?2-fold greater than the PA-IC90. RF AUCs were ?2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT. CONCLUSIONS:DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ?2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.

SUBMITTER: Greener BN

PROVIDER: S-EPMC3804901 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing.

Greener Benjamin N BN Patterson Kristine B KB Prince Heather M A HM Sykes Craig S CS Adams Jessica L JL Dumond Julie B JB Shaheen Nicholas J NJ Madanick Ryan D RD Dellon Evan S ES Cohen Myron S MS Kashuba Angela D M AD

Journal of acquired immune deficiency syndromes (1999) 20130901 1

<h4>Objectives</h4>To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men.<h4>Design</h4>A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days.<h4>Methods</h4>Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collec ...[more]

PMID: 23945251

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Project description:This study describes first dose and steady state pharmacokinetics of raltegravir (RAL) in cervicovaginal fluid (CVF) and blood plasma (BP).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]).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.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.

Dataset Information

Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing.

Publications

Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing.

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