Dwyer, AB

Owen, Andrew

Rannard, SP

Savage, Alison C

Scott, Trevor

Siccardi, M

Tatham, L

Vourvahis, Manoli

University of Liverpool Repository

The introduction of antiretroviral therapy (ART) has significantly reduced HIV-associated morbidityand mortality and has transformed HIV infection into a manageable chronic condition1. However,strict adherence to daily oral ART remains essential in maintaining viral suppression, preventing theemergence of resistance and reducing the risk of HIV transmission2,3. Pre-exposure Prophylaxis(PrEP) has been shown to be effective in the prevention of HIV acquisition in individuals identified asbeing at risk of infection4. MVC has particular appeal for use in PrEP5,6. It is readily absorbed intorelevant tissues and has a unique resistance profile compared to other ARVs meaning resistance israre7,8. Studies have shown a clear dose-response relationship between protection and adherence9.The challenges presented by daily oral dosing and the requirement for life-long maintenance of suchdosing has driven interest in the development of Long-Acting Injectables (LAIs), a technology wellestablished for antipsychotic-therapies and contraception10. Here, we describe the use of emulsion-templated freeze-drying (ETFD) in the development of oil-blended MVC Solid Drug Nanoparticles(SDNs) as potential LAI MVC nanomedicines for use in PrEP.MVC NanodispersionMVC loading (wt.%)Z-average size (nm)PDI1 50% 115 0.2102 50% 160 0.2543 50% 145 0.2134 60% 155 0.1495 60% 170 0.1696 70% 175 0.165Table 1. MVC SDNs characterised using dynamic light scattering (Malvern Instruments, UK)SDN Production and CharacterisationAn ETFD screen was used to produce and optimisesoybean oil blended solid drug nanosuspensions ofMVC, achieving up to 70 wt.% drug-loading.Formulations progressed to In vitro release ratestudies are outlined in Table 1.Dichloromethane-in-water emulsions were preparedvia sonication, consisting of: (i) a 6:1 ratio of MVCand soybean oil within the dispersed organic phase,and (ii) combinations of polymers and surfactantswithin the aqueous continuous phase. Rapid freezingand drying of the emulsions gave SDNs dispersedwithin a solid matrix of hydrophilic polymer andsurfactant stabilisers, which were subsequentlydispersed in water to yield aqueous nanodispersionsand used for pharmacological assessment.In vitro MVC ReleaseUnderstanding a formulation’s release rate can be used topredict the rate of drug release from an intramuscular depot.• MVC release from the 6 formulations and a conventionalMVC preparation (<5% DMSO) was assessed using RapidEquilibrium Dialysis (RED) across a size selectivemembrane (8 kDa MWCO).• The results in Fig 1. indicate a, 2.7-, 3.1-, 2.7-, 1.8-, 1.9-and 1.8-fold reduction in MVC release rate for the SDNformulations 1 through 6 compared to a conventionalMVC preparation, respectively.1. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents What’s New in the Guidelines? Key Updates What to Start: Initial Combination Regimens for the      Antiretroviral-Naive Patient. https://aidsinfo.nih.gov/guidelines.2. C. Trezza, S.L. Ford, W. Spreen, R. Pan, S. Piscitelli, Formulation and pharmacology of long-acting cabotegravir, Curr. Opin. HIV AIDS. 10 (2015) 239–245. 3. M.S. Cohen, Y.Q. Chen, M. Mccauley et al., Prevention of HIV-1 Infection with Early Antiretroviral Therapy, N Engl J Med. 3656365 (2011) 493–505.4. R.M. Grant, J.R. Lama, P.L. Anderson et al, Pre-exposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men, N Engl J Med. 36327 (2010). 5. R.M. Gulick, T.J. Wilkin, Y.Q. Chen et al, Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN     069/ACTG A5305), J. Infect. Dis. 215 (2017).6. R.M. Gulick, T.J. Wilkin, Y.Q. Chen et al, Safety and tolerability of maraviroc-containing regimens to prevent HIV infection in women, Ann. Intern. Med. 167 (2017) 384–393. 7. C.M. Perry, Maraviroc, Drugs. 70 (2010) 1189–1213. 8. J. Fox, J.M. Tiraboschi, C. Herrera et al, Pharmacokinetic/Pharmacodynamic Investigation of Single-Dose Oral Maraviroc in the Context of HIV-1 Pre-exposure Prophylaxis, JAIDS J. Acquir. Immune Defic. Syndr. 73 (2016) 252–257. 9. C.W. Hendrix, Minireview Exploring Concentration Response in HIV Pre-Exposure Prophylaxis to Optimize Clinical Care and Trial Design, Cell. 155 (2013) 515–518. 10. A. Owen, S. Rannard, Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy, Adv. Drug Deliv. Rev. 103 (2016).Conventional MVC 1 2 3 4 5 60.00.10.20.3Release rate (h-1)*** *** ****** *** ***Figure 1. MVC release rate constantcalculated over 6 h for both conventionaland SDN formulated MVC. RED platesincubated at 37oC, 100 rpm. (P=<0.001;unpaired two-tailed t-test).In vivo LAI PharmacokineticsRats were dosed intramuscularly, into the left hindleg with 10 mg Kg-1 MVC either as a conventionalMVC preparation (<5% DMSO) or as oil-blendednanodispersions.• The results in Fig 2. show MVC was detectable in plasma for up to7- and 10-days for nanodispersion 1 and 3, respectively.Nanodispersion 2 displayed comparable exposure with theconventional MVC dose.• The parameters outlined in Table 2 show a 3- and 4.9-foldincrease in the AUC0-∞ for nanodispersions 1 and 3, respectively.• Similarly, a 2.3- and 3.6-fold increase in the terminal half-life (t½)was observed for nanodispersions 1 and 3, respectively. Whereasa 1.6-fold decrease in MVC t½ was observed for nanodispersion 2.• All In vivo work was conducted in accordance with the Animals(Scientific Procedures) Act 1986 (ASPA), UK Home Office.1101000 1 2 3 4 5 6 7 8 9 10MVC plasma concentration (ng/ml)Time (days)ConventionalNanodispersion 11101000 1 2 3 4 5 6 7 8 9 10MVC plasma concentration (ng/ml)Time (days)ConventionalNanodispersion 21101000 1 2 3 4 5 6 7 8 9 10MVC plasma concentration (ng/ml)Time (days)ConventionalNanodispersion 3Pharmacokinetic parameterConventionalMVCNanodispersion 1Nanodispersion 2Nanodispersion 3Cmax (ng ml-1) 71.67 62.88 50.58 69.85AUC0-∞ (ng.h ml-1 567.17 1720.51 628.62 2821.3AUC0-24 (ng.h ml-1) 244.29 472.19 356.76 714.85Terminal half-life (t½) 53.23 121.44 33.19 196.04C24 (ng ml-1) 3.67 9.30 4.11 7.23C48 (ng ml-1) 2.69 7.28 4.08 6.50C72 (ng ml-1) 2.66 4.18 2.84 6.32C168 (ng ml-1) -* 3.81 -* 4.67C240 (ng ml-1) -* -* -* 3.30(-*)=below limits of quantificationTable 2. Pharmacokinetic parameters derived from Figure 2. Figure 2. MVC exposure in adultmale Wistar rats following a singleintramuscular injection of either aconventional MVC preparation oreach nanodispersion. n=3, ±SD.• Oil-blended MVC nanodispersions were developed and investigated as LAI formulations.• Pharmacokinetic studies in rat demonstrate up to 10-days MVC exposure.• These data support development of a MVC LAI formulation with potential application in PrEP.# 483

Towards a Long-Acting Injectable (LAI) Formulation For Maraviroc

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Towards a Long-Acting Injectable (LAI) Formulation For Maraviroc

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