Single and multiple dose pharmacokinetics of dolutegravir in the genital tract of HIV-negative women

Abstract

Background: Antiretrovirals that achieve adequate concentrations in anatomical sites of transmission are of interest for HIV prevention. A Phase I open-label pharmacokinetic (PK) study was performed to describe first dose (PK1) and steady-state (PK2) PKs of the integrase inhibitor dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT) and vaginal tissue (VT) in HIV type-1-negative women.

Methods: A total of 8 healthy females given DTG 50 mg daily for 5-7 days had 11 paired BP and CVF samples collected over 24 h following the first dose (PK1) and multiple dosing (PK2). Each woman underwent CT and VT biopsies at 1/4 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analysed by validated liquid chromatography-tandem mass spectrometry methods. Non-compartmental PK analysis was performed and Spearman rank correlations determined between matrices.

Results: BP areas under the concentration-time curve (AUCs) were similar to previous reports and concentrations remained greater than the protein-adjusted (PA) 90% inhibitory concentration (IC90) for wild-type HIV (64 ng/ml). CVF exposures were approximately 6% of BP with low inter-individual variability. CT and VT exposures were 7% of BP at PK1, and 9-10% of BP at PK2 with 94% of samples >PA-IC90. CT and VT concentrations were correlated to each other (ρ=0.70, P=0.003), and to CVF at steady state (ρ=0.52, P=0.04). Accumulation of DTG from PK1 to PK2 occurred in BP, CT and VT, but only marginally in CVF.

Conclusions: DTG BP PK were consistent with previously published values. CVF, CT and VT exposures were highly correlated. At PK2, DTG accumulated to a greater extent in tissue than in BP or CVF, suggesting increased tissue affinity.

Trial registration: ClinicalTrials.gov NCT01404806.

Figures

Figure 1. Median (IQR) Concentrations of dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT), and vaginal tissue (VT) following a single dose of DTG

Following the first dose of DTG, the median (IQR) DTG concentrations at each time point are plotted for BP and CVF and the median (range) DTG concentrations of the two individual subject CT and VT samples at each time point are plotted as a composite pharmacokinetic curve. Error bars represent IQR for BP and CVF, and the 2 individual samples at each time point for CT and VT. The AUC ratio of CVF to BP is 0.07 (0.05–0.18) following the first dose and the AUC ratio of tissue to CVF is 0.09.

Figure 2. Pharmacokinetics of dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT), and vaginal tissue (VT) at steady state

At steady state, the median (IQR) DTG concentrations at each time point are plotted for BP and CVF and the median (range) DTG concentrations of the two individual subject CT and VT samples at each time point are plotted as a composite pharmacokinetic curve. Error bars represent IQR for BP and CVF, and the 2 individual samples at each time point for CT and VT. The AUC ratio of CVF to BP is 0.06 (0.04–0.11) at steady state and the tissue concentrations are 46–63% higher than in CVF.

Figure 3. The correlation between cervical tissue (CT) and vaginal tissue (VT) dolutegravir (DTG) concentrations

Individual concentration/time points are plotted for DTG in CT and VT. A significant (p=0.003) correlation is noted between CT and VT concentrations (rho=0.70). A line of unity is presented as reference.

Figure 4. The correlation between cervicovaginal fluid (CVF) and genital tissue dolutegravir (DTG) concentrations

Individual concentration/time points are plotted for DTG in genital tract tissues and in CVF. a) Presents cervical tissue (circles) and vaginal tissues (squares) correlated with CVF following the first dose of DTG. b) Presents vaginal tissue (circles) and vaginal tissues (squares) correlated with CVF after multiple dosing. The correlation between CVF and genital tissues (GT) at PK1 is 0.16 (p=0.55), and between CVF and GT at PK2 is 0.52 (p=0.04). A line of unity is presented as reference.