Author: Anam Fayyaz (1, 2), Veli-Pekka Ranta (2), Eva M. del Amo (3), Iain Gardner (1), Arto Urtti (2), Masoud Jamei (1)
Institution: (1) Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom, (2) School of Pharmacy, University of Eastern Finland, Kuopio, Finland, (3) School of Pharmacy, University of Manchester, Manchester, United Kingdom
Introduction:
Eye drops/topical drops are among the most convenient ocular drug administration route, as they are non-invasive, self-administered and show high patient compliance (1, 2). Poor corneal permeability and drainage through the tear outflow cause poor bioavailability and potentially increase adverse effects when drugs are delivered through this route (3, 4). A mechanistic model integrating eye anatomical and physiological parameters with drug properties and formulation characteristics can help getting better insight into drug bioavailability and disposition in the interior eye which is currently lacking (4). In vitro in vivo extrapolation approaches linked with physiologically based pharmacokinetic modeling provides a powerful tool to serve this purpose. Such models can reduce, refine and replace animal studies and inform and speed up ocular drug development (5)
Objectives:
To build a general semi-physiologically based pharmacokinetic model for topical ocular drug delivery of small molecule drugs to rabbit eye. Further, to verify the model predictive performance for topically administered pilocarpine and timolol to rabbit eye.
Material and Methods:
Anatomical and physiological data from rabbit eye were collated and analysed from the literature. A physiologically based model for modelling administration of topical ocular drugs to rabbit eye was developed considering 4 compartments, namely the tear fluid, cornea, aqueous humor and a reservoir compartment. The model was built in Matlab and simulations were run to predict the concentration profiles of drug in different ocular tissues.
Pilocarpine and timolol (in solution) were selected as two model drugs mainly due to availability from the literature of the concentration time profiles for different rabbit ocular tissues. The model requires drug related parameters: 1) permeability from tear fluid to cornea (corneal epithelial rabbit study timolol, ex-vivo study pilocarpine), 2) clearance from tear fluid to conjunctiva (in vivo precorneal clearance study for both), 3) clearance from cornea to aqueous humor (simulation model timolol, apparent rate constant converted to clearance values pilocarpine), 4) clearance from aqueous humor (determined from intracameral injection study for both drugs), 5) volume of distribution in aqueous humor (determined from intracameral injection study for both drugs), 6) volume and flows in and out of the reservoir (determined from intracameral injection study for both drugs).
Results:
The model performance for pilocarpine and timolol models were compared against the reported observed values. The observed Cmax and AUC in aqueous humor for pilocarpine were 1.11 µg/ml and 63.2 µg.min/ml. While the predicted values are 1.20 µg/ml and 76.08 µg.min/ml respectively. The observed Cmax and AUC in aqueous humor for timolol were 3.0 µg/ml and 322.1 µg.min/ml. While the predicted values are 3.67 µg/ml and 420.343 µg.min/ml respectively. These results show that the predictions were acceptable with less than 2-fold difference then the observations.
Conclusion:
A semi-PBPK model for topical ocular drug delivery of small molecules to rabbit eyes was developed for pilocarpine and timolol. The model is able to simulate the distribution of drugs in different tissues of the eye after instillation of a drug solution in the eye (with acceptable predictability). We will assess the model performance for a wider range of drugs and expand it to other anterior eye tissue compartments.
References:
[1] Le Bourlais, C., et al. (1998). “Ophthalmic drug delivery systems—recent advances.” Prog Retin Eye Res 17(1): 33-58.
[2] Patel, A., et al. (2013). “Ocular drug delivery systems: an overview.” World journal of pharmacology 2(2): 47.
[3] Sasaki, H., et al. (1997). “In vivo ocular pharmacokinetic model for designing dosage schedules and formulations of ophthalmic drugs in human.” Acta medica Nagasakiensia 42(3-4): 45-50.
[4] Del Amo, E. M., et al. (2015). “Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development.” European Journal of Pharmaceutics and Biopharmaceutics 95: 215-226.
[5] Del Amo, E. M., et al. (2017). “Pharmacokinetic aspects of retinal drug delivery.” Prog Retin Eye Res 57: 134-185.
Reference: PAGE 28 (2019) Abstr 8996 [www.page-meeting.org/?abstract=8996]
Poster: Drug/Disease Modelling - Other Topics