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Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV

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Abstract

Background and Objectives

Antiretrovirals are currently used for the treatment and prevention of HIV infection. However, poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying antiretroviral administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight antiretrovirals through physiologically based pharmacokinetic (PBPK) modelling.

Methods

A whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulations

Results

The predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control their release rate can be addressed.

Conclusions

These data may help inform the target product profiles for LA antiretroviral reformulation strategies.

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Acknowledgments

This work was supported by the US National Institutes of Health (AI 114405-01).

Conflict of interest

Andrew Owen has received research funding from Merck, Pfizer and AstraZeneca, consultancy from Merck and Norgine, and is a co-inventor of patents relating to HIV nanomedicines. Marco Siccardi has received research funding from ViiV and Janssen. David J. Back is a board member for Abbvie, Boehringer Ingelheim, Gilead, Janssen, Merck and ViiV. He receives consulting or advisor fees from Abbvie, Boehringer Ingelheim, Gilead, Janssen, Merck and ViiV. He also received research funding from Abbvie, Boehringer Ingelheim, BMS, Gilead, Janssen, Merck and ViiV. Charles Flexner received consulting or advisor fees from Abbvie, Boehringer Ingelheim, Bristol Myers-Squibb, Gilead, GlaxoSmithKline, Merck and ViiV. Rajith K.R. Rajoli, Steve Rannard and Caren L. Freel Meyers have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK

    Rajith K. R. Rajoli, David J. Back, Andrew Owen & Marco Siccardi

  2. Department of Chemistry, University of Liverpool, Crown Street, Liverpool, UK

    Steve Rannard

  3. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Caren L. Freel Meyers

  4. Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, MD, USA

    Charles Flexner

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  1. Rajith K. R. Rajoli
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  2. David J. Back
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  6. Andrew Owen
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Correspondence to Marco Siccardi.

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Rajoli, R.K.R., Back, D.J., Rannard, S. et al. Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV. Clin Pharmacokinet 54, 639–650 (2015). https://doi.org/10.1007/s40262-014-0227-1

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