title: Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Rajith K R
authors.initials: RK
authors.lastname: Rajoli
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Steve
authors.initials: S
authors.lastname: Rannard
authors.forename: Caren L
authors.initials: CL
authors.lastname: Freel Meyers
authors.forename: Charles
authors.initials: C
authors.lastname: Flexner
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D003198:Computer Simulation; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007273:Injections, Intramuscular; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D050997:Nanomedicine / Q000379:methods; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents