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. 2017 Feb;42(1):59-68.
doi: 10.1007/s13318-016-0319-4.

Ocular Drug Distribution After Topical Administration: Population Pharmacokinetic Model in Rabbits

Nassim Djebli  1 , Sonia Khier  2   3 , Florence Griguer  1 , Anne-Laure Coutant  1 , Alexandra Tavernier  1 , Gerard Fabre  1 , Caroline Leriche  4 , David Fabre  1
Affiliations

Ocular Drug Distribution After Topical Administration: Population Pharmacokinetic Model in Rabbits

Nassim Djebli et al. Eur J Drug Metab Pharmacokinet. 2017 Feb.

Abstract

Background and 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.

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Conflict of interest statement

Compliance with Ethical Standards Funding No sources of funding were received for the conduct of this study. Conflicts of interest ND, SK, FG, A-LC, AT, GF, CL and DF have no potential conflicts of interests to declare. Ethical approval The experimental design was approved by the local “Comité d’Ethique pour la Protection des Animaux de Laboratoire” (Animal Care and Use Committee) and the study was performed in accordance with the internal Charter on the Humane Care and Use of Laboratory Animals.

Figures

Fig. 1
Fig. 1
Multi-compartimental model of eye selected. F 1 relative bioavailability in the tears, k 12 (h−1) rate constant (tear to the naso-lacrymal duct) in nanosuspensions, k 12 (h−1) rate constant (tear to the naso-lacrymal duct) in solution, k 13 (h−1) rate constant (tear to cornea), Q (µL/h) inter-compartmental clearance (cornea/aqueous humor), Cl nl (µL/h) clearance from naso-lacrymal duct, Cl ah (µL/h) clearance from aqueous humor, Cl c clearance from cornea compartment = 0.1 × Cl ah, V 1 (µL) volume of distribution (tear), V 2 (µL) volume of distribution of naso-lacrymal duct, V 3 (µL) volume of distribution of cornea, V 4 (µL) volume of distribution of the aqueous humor
Fig. 2
Fig. 2
Relationship between individual predicted (IPRED, red solid dots) and population predicted (PRED, blue open circles) versus observed tissue concentrations in log–log scale in tears, nasolacrimal duct, cornea and aqueous humor
Fig. 3
Fig. 3
Relationship between individual weighted residuals (IWRES) and individual predicted concentrations in log scale (a); relationship between conditional weighted residuals (CWRES) and population predicted concentrations in log scale (b) from pooled data set (tears, nasolacrimal duct, cornea, and aqueous humor) of the 84 rabbit eyes
Fig. 4
Fig. 4
Prediction corrected visual predictive check of the final model (log scale) in the tears, in the nasolacrimal duct, in the cornea and in aqueous humor. Blue areas represent the 95 % CI of the 5th and 95th percentiles of the predictions; pink area represents the 95 % CI of the median of predictions; purple area represents the overlap between blue and pink areas; blue dots are observed tissue concentrations; solid red line represents the median of observations and dashed red lines represent the 5th and 95th percentiles of observations
Fig. 5
Fig. 5
Predicted tissue concentration–time profiles (solid lines) and observed concentrations (dots) in the tears, nasolacrimal duct with solution formulation (red) and with nanosuspension formulation (blue), cornea and aqueous humor in each eye
Fig. 6
Fig. 6
Predicted tissue concentration–time profiles in the tears, nasolacrimal duct, cornea and aqueous humor for a typical rabbit eye with the solution or nanosuspensions
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