Combination Pod-Intravaginal Ring Delivers Antiretroviral Agents for HIV Prophylaxis: Pharmacokinetic Evaluation in an Ovine Model

Abstract

Preexposure prophylaxis (PrEP) against HIV using oral regimens based on the nucleoside reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF) has been effective to various degrees in multiple clinical trials, and the CCR5 receptor antagonist maraviroc (MVC) holds potential for complementary efficacy. The effectiveness of HIV PrEP is highly dependent on adherence. Incorporation of the TDF-MVC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described. The pharmacokinetics and preliminary local safety characteristics of a novel pod-IVR delivering a combination of TDF and MVC were evaluated in the ovine model. The device exhibited sustained release at controlled rates over the 28-day study and maintained steady-state drug levels in cervicovaginal fluids (CVFs). Dilution of CVFs during lavage sample collection was measured by ion chromatography using an inert tracer, allowing corrected drug concentrations to be measured for the first time. Median, steady-state drug levels in vaginal tissue homogenate were as follows: for tenofovir (TFV; in vivo hydrolysis product of TDF), 7.3 × 10(2) ng g(-1) (interquartile range [IQR], 3.0 × 10(2), 4.0 × 10(3)); for TFV diphosphate (TFV-DP; active metabolite of TFV), 1.8 × 10(4) fmol g(-1) (IQR, 1.5 × 10(4), 4.8 × 10(4)); and for MVC, 8.2 × 10(2) ng g(-1) (IQR, 4.7 × 10(2), 2.0 × 10(3)). No adverse events were observed. These findings, together with previous pod-IVR studies, have allowed several lead candidates to advance into clinical evaluation.

Trial registration: ClinicalTrials.gov NCT02431273.

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Sheep TDF-MVC pod-IVR study timelines and biological sample collection points (n = 4). Regular black arrows, in order of collection, blood, vaginal fluid (two Weck-Cel samples per time point—one dorsal, one ventral), and cervicovaginal lavage fluid; gray arrows, collection of vaginal tissue samples (four pinch biopsy samples per time point on day 14 and day 28; whole tissues on day 35); arrows with circles, colposcopic/laparoscopic examination.

FIG 2

High-definition colposcopy images of the vaginal vault showing the cervix (i) and the mucous-covered pod-IVR (ii) in place. The location of one of the 10 pod cavities is identified (iii). The nylon suture (iv) attached to the IVR facilitated removal and was used to monitor expulsion(s).

FIG 3

Box plots (8 or 9 CVL fluid samples collected over the 35-day study; see Fig. 1) of CVF volumes collected using the lavage procedure. 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. OC1 to OC4, medicated IVRs; OC5 to OC8, unmedicated IVRs.

FIG 4

Distribution of ARV drug levels (A, TDF; B, TFV; C, MVC) in undiluted vaginal fluids collected ventrally (black symbols) and dorsally (gray symbols) in the midvagina using Weck-Cel sponges. d, day.

FIG 5

Distribution of ARV drug levels (means + standard deviations [SD], n = 4) in CVL fluid samples that were uncorrected (A) and normalized for dilution using a Li+ tracer added to the CVL fluid (B). Black closed circles, TDF; black open circles, TFV; gray open circles, MVC.

FIG 6

Distribution of ARV drug levels in vaginal tissue biopsy samples. Open circles, MVC (quantified in nanograms per gram); closed circles, TFV (nanograms per gram); triangles, TFV-DP (femtomoles per gram) (1 fmol g−1 TFV-DP is equivalent to 4.5 ×10−4 ng g−1). Horizontal bars represent means.