CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

483 TOWARDS A LONG-ACTING INJECTABLE (LAI) FORMULATION FOR MARAVIROC Lee M. Tatham , Andrew Dwyer, Alison C. Savage, Marco Siccardi, Steve Rannard, Andrew Owen University of Liverpool, Liverpool, UK Background: Suboptimal adherence to antiretroviral therapy can lead to insufficient drug exposure, leading to viral rebound and increasing the likelihood of resistance. This has driven the development of long-acting injectable (LAI) formulations, which may mitigate the problems with suboptimal patient adherence. Currently, Maraviroc (MVC) is orally dosed with an estimated oral bioavailability of 33%. Given the different resistance profile of MVC compared to more commonly used therapies, a MVC LAI formulation has particular appeal for implementation in Pre-Exposure Prophylaxis (PrEP). The aims of this study were to assess the potential of oil blended MVC Solid Drug Nanoparticles (SDNs) for LAI administration. Methods: An emulsion-templated freeze-drying screen was successfully employed to produce soybean oil blended SDNs with 50 wt.% [ 3 H]-MVC loading. Rapid Equilibrium Dialysis (RED) was used to determine the rate of MVC release with diffusion across a size selective membrane. Subsequently, male Wistar rats were dosed intramuscularly in the biceps femoris (10 mg/kg MVC) with either an aqueous MVC preparation (<5% DMSO) or the lead SDNs. Plasma samples were taken and analysed via scintillation counting until [ 3 H]-MVC concentrations fell below the limits of quantification. Results: RED assays revealed three MVC SDNs with slower release rates than a conventional MVC preparation, with the first-order release rate constant, derived from the final sample, over 3-fold lower. Intramuscular injection of the nanosuspensions revealed significant variations in MVC exposure (Table 1). Following the initial burst event (<24 hours), nanosuspensions 1 and 3 were shown to continue releasing MVC at a steady rate for up to 7 and 10 days with over a 3- and 4-fold increase in MVC AUC t-∞ compared to the unformulated MVC preparation, respectively. However, nanosuspension 2 was undetectable in plasma after 3 days with an AUC t-∞ value comparable to the conventional MVC preparation. Conclusion: The data presented here highlight the development and optimisation of LAI MVC. In vivo analysis of the lead formulations demonstrated that the SDN technology is capable of attaining and sustaining MVC exposure for up to 10 days in rats. Using these data, modelling potential MVC exposure in humans is planned with the aim of achieving a bi-monthly or monthly LAI format.

Poster Abstracts

482 MARAVIROC SOLID DRUG NANOPARTICLES WITH IMPROVED ORAL PHARMACOKINETICS Lee M. Tatham , Alison C. Savage, Andrew Dwyer, Marco Siccardi, Steve Rannard, Andrew Owen University of Liverpool, Liverpool, UK Background: Maraviroc (MVC) is an orally dosed selective CCR5 antagonist used against CCR5-trophic HIV type-1. MVC is a P-glycoprotein (P-gp) and a CYP3A4 substrate, which limit effective absorption. It is estimated that over 60% of the absorbed drug is metabolised at first pass, resulting in a bioavailability of ~33%. Additionally, C max -driven postural hypotension has been described. The aims of this study were to apply an emulsion-templated freeze-drying technique, with and without oil-blending, to develop and optimise MVC-loaded Solid Drug Nanoparticles (SDNs) for improved oral pharmacokinetics (PK). Methods: An emulsion-templated freeze-drying screen was successfully employed to produce twelve different SDN dispersions of [ 3 H]-MVC, with up to 70 wt.% drug-loading. Additionally, six of the SDNs were blended with soybean oil to identify if oil-blending influences MVC exposure. The apparent permeability (Papp) of each SDN and a conventional MVC preparation (<0.5% DMSO) was determined using Caco-2 monolayers as a model for gut epithelium. Subsequently, male Wistar rats were orally dosed with either an aqueous MVC preparation (<5% DMSO) or the lead SDN which produced the greatest fold increase in MVC Papp. Results: Dynamic light scattering indicated that MVC SDNs were successfully prepared with z-average sizes ranging from 125 to 956 nm. Significant variations in MVC Papp were observed across the different SDNs investigated, with up to 1.7- and 6.5-fold increases in Papp for the SDNs and the oil-blended SDNs, respectively. Oral dosing of rats with the lead SDNs revealed enhanced MVC exposure compared to rats dosed with a conventional MVC preparation (Table 1). The C max :C min ratio for nanodispersion 1 was over 1.5-fold lower compared to the conventional MVC preparation but over 4.5-fold greater for nanodispersion 2. Additionally, increased MVC concentrations were observed in most dissected tissues obtained from the SDN dosed rats. Conclusion: These data highlight the development and optimisation of 70 wt.%MVC-loaded SDNs. The potential for improved oral absorption was identified and the lead nanosuspensions were shown to improve MVC exposure following oral dosing. Oil blended SDNs appeared to further modify the PK of MVC, warranting further investigation. This study has highlighted the potential of SDN technology for improving MVC PK, and the scope for dose reduction while reducing the C max to C min ratio.

484 IN VIVO PHARMACOKINETICS OF NOVEL LONG-ACTING INJECTABLE EMTRICITABINE PRODRUGS Paul Curley 1 , James J. Hobson 1 , Christopher David 1 , Amer Al-Khouja 2 , David Meyers 2 , Caren Freel Meyers 2 , Charles W. Flexner 2 , Marco Siccardi 1 , Steve Rannard 1 , Andrew Owen 1 1 University of Liverpool, Liverpool, UK, 2 Johns Hopkins Hospital, Baltimore, MD, USA

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