Abstract
Purpose :
Traditional pharmacokinetic (PK)-pharmacodynamic (PD) models available for studying drug transport and its response, group anatomical and physiological processes to minimize the computational complexity. We present a new PBPK-PD model to predict the transport of glaucoma medication and the resulting IOP reduction / dynamics.
Methods :
Cornea, lens, and iris were modeled as isotropic linearly elastic solids, and aqueous humor flow modeled as an isotropic Newtonian viscous fluid flow. Interaction between ocular structures and aqueous humor flow dynamics was modeled as a time-dependent computational fluid-structure interaction (FSI) problem. Flow through the trabecular meshwork (TM), which was modeled as a porous media with adjustable permeability and porosity parameters, was governed by the Darcy pressure gradient term. Aqueous humor (AH) production in the ciliary body was modeled as an adjustable mass flow rate boundary condition of 5e-7 kg/s. Drug transport was modeled using a convection-diffusion equation coupled with the FSI model. An estimate of the total drug transported to the anterior chamber and TM obtained using our PBPK model was used to stimulate an effector system to activate the drug-response pathway. An indirect response PD model was used to predict the drug response. AH production was adjusted to achieve the desired IOP response to the drug. PBPK-PD method was evaluated using study rabbit eyes from Sakanaka K, 2008. Baseline IOP in the PBPK-PD model was set to 21 mmHg (TM permeability of 4.9e-14 m2; porosity of 0.01) . A 25μl of 0.5% Timolol Maleate drop was administered at baseline and the drug transport and AH dynamics were observed for 420 minutes.
Results :
Fig. 1 shows the drug distribution in the anterior segment at baseline and at 23.5 minutes. Fig. 2 shows AH dynamics after administering 0.5% Timolol. The IOP dynamics predicted by our PBPK-PD method was similar to the observed IOP changes in the study rabbit eyes (Sakanaka K, et al).
Conclusions :
Our PBPK-PD model can provide a realistic estimate of drug transport and predict aqueous humor dynamics and drug response for any dosage regimen specific to each study eye (altered aqueous flow dynamics and IOP response). Our model can be useful for identifying candidate drugs, an optimal dosage level and optimizing drug delivery to achieve a desired drug response.
This is a 2020 ARVO Annual Meeting abstract.