The effect of the foreign body response on drug elution from subdermal delivery systems

Contrasting findings are presented in the literature regarding the influence of foreign body response (FBR) on drug release from implantable drug delivery systems. To this end, here we sought direct evidence of the effect of the fibrotic tissue on subcutaneous drug release from long-acting drug delivery implants. Specifically, we investigated the pharmacokinetic impact of fibrotic encapsulation on a small molecule drug, islatravir (293 Da), and a large protein, IgG (150 kDa), administered via biocompatible implants. First, solid implants fabricated from biocompatible PMMA resin, nylon, and PLA were used to characterize the degree of FBR in rats. Despite initial material-dependent differences in the early FBR phase, the thickness and composition of the fibrotic capsules normalized in the chronic phase of FBR. Ex vivo assessments indicated an increase in the diffusivity of both molecules over time, aligning with a reduction in collagen density within the fibrotic tissue. Subsequently, reservoir-based drug delivery devices, matching the solid implants in size, shape and material, were implanted to study in vivo pharmacokinetics. The study revealed consistent plasma levels of islatravir across different implant materials and a temporary modulation of IgG release from PMMA resin implants during the acute FBR phase. End-point histological analyses confirmed that the localized delivery neither incited inflammation in the surrounding tissue nor did it alter vascularization. This evidence suggests that, while acute FBR may transiently affect the release of larger molecules, in the absence of acute local inflammation, fibrotic encapsulation does not significantly impact the steady-state release of small molecule drugs from long-acting implantable delivery systems.