Abstract
Purpose :
In ophthalmic drug discovery and development, it is crucial to understand local drug distribution in the eye. In the preclinical research phase, measuring drug concentrations in target tissue describes the total exposure, but often the more relevant free drug concentration remains unclear. Furthermore, it is difficult to measure drug exposure at all at the ocular target site later in the clinical phase. Pharmacokinetic models may be used to provide insight into drug exposure and the active free concentration at the target site. We developed a PBPK model of the rat eye to better understand ocular distribution of small molecules.
Methods :
We measured concentrations of dexamethasone, levofloxacin, BI1 and BI2 (in-house drug candidates), in plasma and eight different ocular tissues (cornea, aqueous humor, iris-ciliary body, lens, vitreous, retina, RPE-choroid and sclera) in albino Wistar Han and pigmented Brown Norway rats at 4-7 time points after oral administration. First, we fit empirical compartment models to plasma concentrations from each study and fixed them thereafter. Second, we developed a PBPK model of the rat eye to fit observed ocular tissue concentrations using physiological parameters (from literature or in-house measurements) and compound-specific parameters (measured in vitro or fitted to observed concentrations).
Results :
Model predicted ocular concentrations in albino as well as pigmented rats were mostly within two-fold of observed. For each compound, we fitted tissue-specific unbound fractions (futissue) for the lens, cornea and sclera, and a shared futissue for iris-ciliary body, retina and RPE-choroid. Additionally, we included efflux in the blood-ocular barriers to emulate potential effects of compounds being substrates of relevant drug transporters such as P-glycoprotein. For data from pigmented rats, we considered melanin binding in the iris-ciliary body and RPE-choroid.
Conclusions :
We were able to fit ocular tissue concentrations of four small molecules with the developed rat eye PBPK model. The model can be used to support preclinical drug research and serve as a starting point for predicting human ocular concentrations. Due to the physiologically-based structure, the model can also give insights into the distribution of intravitreally applied drugs.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.