title: Ocular Drug Distribution After Topical Administration: Population Pharmacokinetic Model in Rabbits.
abstract: OBJECTIVE
  When eye diseases are treated by topical administration, the success of treatment lies in the effective drug concentration in the target tissue. This is why the drug's pharmacokinetic, in the different substructures of the eye, needs to be explored more accurately during drug development. The aim of the present analysis was to describe by rabbit model, the distribution of a drug after ocular instillation in the selected eye tissues and fluids.
  
  
  METHODS
  By a top-down population approach, we developed and validated a population pharmacokinetics (PopPK) model, using tissue concentrations (tear, naso-lacrymal duct, cornea and aqueous humor) of a new src tyrosine kinase inhibitor (FV-60165) in each anterior segment's tissue and fluid of the rabbit eye. Inter-individual variability was estimated and the impact of the formulation (solution or nanosuspension) was evaluated.
  
  
  RESULTS
  The model structure selected for the eye is a 4-compartment model with the formulation as a significant covariate on the first-order rate constant between tears and the naso-lacrymal duct. The model showed a good predictive performance and may be used to estimate the concentration-time profiles after single or repeated administration, in each substructure of the eye for each animal included in the analysis.
  
  
  CONCLUSIONS
  This analysis allowed describing the distribution of a drug in the different selected tissues and fluids in the rabbit's eyes after instillation of the prodrug as a solution or nanosuspension.
authors.affiliation: Disposition Safety and Animal Research, Sanofi Recherche and Developpement, Montpellier, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Djebli
authors.affiliation: Department of Pharmacokinetics, Université de Montpellier, 34090, Montpellier, France. sonia.khier@univ-montp1.fr.|INSERM, U1194, IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298, Montpellier, France. sonia.khier@univ-montp1.fr.
authors.forename: Sonia
authors.initials: S
authors.lastname: Khier
authors.affiliation: Disposition Safety and Animal Research, Sanofi Recherche and Developpement, Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Griguer
authors.affiliation: Disposition Safety and Animal Research, Sanofi Recherche and Developpement, Montpellier, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Coutant
authors.affiliation: Disposition Safety and Animal Research, Sanofi Recherche and Developpement, Montpellier, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tavernier
authors.affiliation: Disposition Safety and Animal Research, Sanofi Recherche and Developpement, Montpellier, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Fabre
authors.affiliation: Research and Drug Discovery, Ophthalmology Division, Sanofi Paris, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Leriche
authors.affiliation: Disposition Safety and Animal Research, Sanofi Recherche and Developpement, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Fabre
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D005123:Eye / Q000378:metabolism*; D008954:Models, Biological; D009301:Nasolacrimal Duct / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011817:Rabbits; D012996:Solutions; D013535:Suspensions; D013666:Tears / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D012996:Solutions; D013535:Suspensions
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