学会抄録

<p><b>Pod-IVR Pharmacokinetics in macaques</b> (A) <i>In vivo</i> release of TDF and FTC from each pod-IVR (N = 6/time point) over the course of the efficacy study determined by residual drug measurements from the pod-IVRs that were in place for 19 weeks with IVRs exchanged for new devices every 2 weeks. The top and bottom of the boxes show the 75th and 25th percentiles, respectively, and the line in the middle of the box is the median value. The dotted lines show the mean (N = 6) <i>in vivo</i> release from identical pod-IVRs obtained during the PK study preceding this efficacy study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157061#pone.0157061.ref026" target="_blank">26</a>]. (B) <i>In vivo</i> release profile for individual macaques (T1-T6) shows variability between animals. (C) TDF, TFV, TDF+TFV, and FTC levels in vaginal fluids collected at each ring exchange. Vaginal fluids were collected with Weck-Cel sponges proximal and distal to the pod-IVR placement. The dotted horizontal lines correspond to the medians from our previous PK study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157061#pone.0157061.ref026" target="_blank">26</a>]. Left panels-proximal; Right panels-distal; Dots-median.</p

Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and unintended pregnancy: Pharmacokinetic evaluation in a macaque model

<div><p>Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF₂) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (<i>N</i> = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean <i>in vivo</i> release rates (mg d^-1) for the two formulations over 30 days ranged as follows: TAF₂ 0.35–0.40; ACV 0.56–0.70; EE 0.03–0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL^-1 prior to IVR insertion and 0.075 ± 0.064 ng mL^-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF₂ and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg^-1; ACV, 0.2 ng mg^-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women’s sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.</p></div

Summary of drug and drug metabolite concentrations at all sampled anatomic sites (six animals).

<p>Summary of drug and drug metabolite concentrations at all sampled anatomic sites (six animals).</p

Pigtailed macaque TAF2-ACV-ENG-EE pod-IVR study timelines and biological sample collection points (<i>N</i> = 6).

<p>Configuration A pod-IVRs (rapid-releasing ENG) were inserted on Day 0 and replaced on Day 14 with Configuration B pod-IVRs (slow-releasing ENG). The Configuration B IVRs were removed on Day 30 and animals were euthanized on Day 34 (animal ID BB495 and DC42), Day 35 (animal ID PHz1 and PPk2), and Day 36 (animal ID PEc2 and BB0539). Blue arrows, in order of collection, blood, pH, and vaginal fluid (two Weck-Cel samples per time point—two proximal and two distal to the IVR). Green arrows, colposcopy examination (right after blood collection). Red arrows, vaginal tissues (six pinch biopsies per time point—three proximal and three distal to the IVR). Complete vaginal tracks were collected at necropsy. Pale blue and pale red arrows correspond to sample collection points with the IVR removed.</p

Plasma progesterone concentrations over 40-week period.

<p>Each panel represents one animal; the arrow indicates the placement of the Configuration A pod-IVR (week 0).</p

<i>In vivo</i> IVR drug release rates in the context of previous studies.

<p><b>(A) Molar daily <i>in vivo</i> release of TDF from a previous pod-IVR study in pigtailed macaques [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185946#pone.0185946.ref039" target="_blank">39</a>] compared to TAF</b>_<b>2</b><b>release rate in the present study.</b> An unpaired <i>t</i> test with Welch’s correction shows that while the release rates are not statistically significantly different (<i>P</i> = 0.0734), they are similar, with the mean TAF₂ release rate (red horizontal bar) being lower than the mean TDF release rate (blue horizontal bar) from the TDF-FTC pod-IVRs. Each circle corresponds to an individual datum; pale error bars correspond to standard deviations from the mean. (B) Paired ENG:EE <i>in vivo</i> release rate ratios for Configuration A (blue) and Configuration B (red) pod-IVRs. The ratios span the <i>in vivo</i> ENG:EE release rate ratio for the NuvaRing® in women (green broken horizontal line). Each circle corresponds to an individual datum; horizontal lines, means; pale error bars, standard deviations from the mean.</p

Analytical ranges for biological samples.

<p>Analytical ranges for biological samples.</p

Intracellular TFV-DP concentrations in vaginal tissues and inguinal and iliac lymph nodes collected at necropsy.

<p>Blue, Day 34 (<i>N</i> = 2); red, Day 35 (<i>N</i> = 2); and green, Day 36 (<i>N</i> = 2). The intracellular TFV-DP levels are maintained 4–6 days after pod-IVR removal on Day 30. The box plots represent the analytical lower limits of quantitation (LLOQ) associated with the TFV-DP measurements, where the box extends from the 25th to 75th percentiles, with the horizontal line in the box representing the median; whiskers represent the lowest and highest datum. The assay has an LLOQ of 50 fmol per sample, which is divided by the number of cells collected in each sample to afford the individual LLOQs represented here.</p

TAF2-ACV-ENG-EE pod-IVR <i>in vivo</i> daily drug release rates based on residual drug measurements on used IVRs.

<p>Blue circles, TAF₂; red circles, ACV; green circles, ENG; orange circles, EE. Horizontal lines represent means.</p

<i>In vitro</i> and <i>in vivo</i> daily release rates from Configuration A and Configuration B MPT pod-IVRs.

<p><i>In vitro</i> and <i>in vivo</i> daily release rates from Configuration A and Configuration B MPT pod-IVRs.</p