Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy

Abstract

The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug–polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.

Insight into treatment ofHIVinfection from viral dynamics models

“…Long‐acting therapy, which is taken much less frequently than current daily dosing due to extended half‐life formulations, is currently under development, and there are worries it may be more prone to resistance development in the presence of missed doses. Models can be used to explore this possibility, and for preliminary investigation of a once‐weekly formulation of the drugs dolutegravir and raltegravir, and suggest failure rates should be similar to daily pills with similar average drug concentrations . The periodic highs and lows of drug levels during regular therapy can also promote resistance in an unexpected way.…”

“…Models can be used to explore this possibility, and for preliminary investigation of a once-weekly formulation of the drugs dolutegravir and raltegravir, and suggest failure rates should be similar to daily pills with similar average drug concentrations. 102 The periodic highs and lows of drug levels during regular therapy can also promote resistance in an unexpected way. For example, viral populations may be able to evolve the ability to "synchronize" their lifecycle with the drug period, so that they only undergo a particular lifecycle stage when drug level blocking it is at their lowest, and therefore avoid the drug effect.…”

Retentive drug delivery systems based on shape memory materials

“…Expansion‐dependent retention tools also underlie a number of cutting‐edge engineered devices, and related construction materials, aimed at gastric residence times beyond 24 h up to several weeks . In this respect, star‐shaped and spherical fenestrated structures, subject to in situ reversible expansion due to elastic unfolding, and a pufferfish‐like hydrogel system having high‐speed, high‐ratio, and durable water swelling have been described, for human and/or veterinary application . All of them would notably match the "Ultra‐long‐acting oral formulation" category of FDA's Emerging Technology Program, which has been launched by the agency to endorse adoption of innovative pharmaceutical design and manufacturing schemes entailing purposely set regulatory evaluation approaches .…”

Harnessing nanostructured systems for improved treatment and prevention of HIV disease

“…The Langer lab recently reported a millimeter scale, multi‐ARV weekly oral drug delivery device with different arms made from different polymer components with varying degradation rates to control and sustain release for the desired duration . Another proposed alternative is a sub‐dermal implant of TFV alafenamide capable of releasing 0.92 mg of drug per day with demonstrable zero‐order release kinetics, but that necessitates surgical implantation and removal .…”

“…However, issues arising from polymer toxicity, poor scalability, limited storage stability, low loading efficiency, and accumulation of nanomaterials in major organs are barriers to the development of the field 11. Some have even abandoned nanostructured systems altogether in favor of systems with better potential for progression through clinical trials.The Langer lab recently reported a millimeter scale, multi-ARV weekly oral drug delivery device with different arms made from different polymer components with varying degradation rates to control and sustain release for the desired duration 140. Another proposed alternative is a sub-dermal implant of TFV alafenamide capable of releasing 0.92 mg of drug per day with demonstrable zero-order release kinetics, but that necessitates surgical implantation and removal 141.…”