TY - JOUR
T1 - Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV
AU - Rajoli, Rajith K.R.
AU - Back, David J.
AU - Rannard, Steve
AU - Freel Meyers, Caren L.
AU - Flexner, Charles
AU - Owen, Andrew
AU - Siccardi, Marco
N1 - Publisher Copyright:
© 2014, Springer International Publishing Switzerland.
PY - 2015/12/19
Y1 - 2015/12/19
N2 - 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.
AB - 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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U2 - 10.1007/s40262-014-0227-1
DO - 10.1007/s40262-014-0227-1
M3 - Article
C2 - 25523214
AN - SCOPUS:84930086174
SN - 0312-5963
VL - 54
SP - 639
EP - 650
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 6
ER -