Compartmental transport model of microbicide delivery by an intravaginal ring

Abstract

Topical antimicrobials, or microbicides, are being developed to prevent HIV transmission through local, mucosal delivery of antiviral compounds. While hydrogel vehicles deliver the majority of current microbicide products, intravaginal rings (IVRs) are an alternative microbicide modality in preclinical development. IVRs provide a long-term dosing alternative to hydrogel use, and might provide improved user adherence. IVR efficacy requires sustained delivery of antiviral compounds to the entire vaginal compartment. A two-dimensional, compartmental vaginal drug transport model was created to evaluate the delivery of drugs from an intravaginal ring. The model utilized MRI-derived ring geometry and location, experimentally defined ring fluxes and vaginal fluid velocities, and biophysically relevant transport theory. Model outputs indicated the presence of potentially inhibitory concentrations of antiviral compounds along the entire vaginal canal within 24 h following IVR insertion. Distributions of inhibitory concentrations of antiviral compounds were substantially influenced by vaginal fluid flow and production, while showing little change due to changes in diffusion coefficients or ring fluxes. Additionally, model results were predictive of in vivo concentrations obtained in clinical trials. Overall, this analysis initiates a mechanistic computational framework, heretofore missing, to understand and evaluate the potential of IVRs for effective delivery of antiviral compounds.

Figure 1

Axial (a) and Sagittal (b) MRI images of NuvaRing® placement within the vagina. Reprinted from, with permission from Elsevier.

Figure 2

Finite element mesh used in this computational analysis. The mesh shows a cross-sectional view of an IVR within vaginal tissue. The IVR is represented as the two small circles at the midline of the image; the ring plane is perpendicular to the page. A thin fluid layer runs the length along the midline of the mesh. The remaining area represents vaginal tissue.

Figure 3

Enlarged region of 2-D mesh showing all three compartments. The solid cross-section of the ring is shown with the surround layer of vaginal fluid. Again, the plane of the ring extends out of the page. Vaginal tissue surrounds the ring and thin layer of fluid.

Figure 4

Fluid flow in a channel with porous walls

Figure 5

Results from the computational analysis of microbicide delivery by an intravaginal ring. Colored regions denote dapivirine levels >100*IC₅₀; actual concentrations are given by the scale bars on the right. As a quantitative measure, the percentage of vaginal epithelium with inhibitory concentrations of dapivirine is shown above each plot. Unless otherwise stated, all plots show dapivirine concentrations 24 hours post insertion using a IVR with flux = 50μg/day, a fluid thickness of 2mm, and vaginal fluid production rate of 6mL/day. The influence of several factors on dapivirine delivery was evaluated: A) Effect of time. Protection via IVR delivery is not instantaneous. Approximately 24 hours is needed for most of the vulnerable epithelium to be protected. At 4 hours, only about 37% of the tissue is protected, while after 24 hours almost all (92%) tissue is exposed to inhibitory concentrations. B) Effect of diffusion coefficient. The diffusion coefficient of dapivirine was increased and decreased by 2-fold. Changes in rate of diffusion had minimal effect on the range of inhibitory drug concentrations after 24 hours. C) Influence of vaginal fluid production rate. Greater fluid flow rates allow the IVR to protect a greater amount of vaginal epithelium after 24hrs. D) Influence of IVR flux. The fraction of vaginal tissue that is protected by inhibitory concentrations of drug is only slightly influenced by a two-fold increase or decrease of dapivirine flux from the ring. All doses provided significant protection along the entire vaginal canal at 24 hours. E) Effect of fluid layer thickness. Two-fold differences in fluid layer thickness also had minor effects on overall protection.