Incorporating Computational Fluid Dynamic Modeling into Pharmacometrics Models for Applications to Gene Therapy, Anti-Inflammatory Treatments and Transdermal Patch Drug Delivery
Authors: Park Taeshin , Ko Glen , Zhang Zhiwei , Jiang Jiaolong , Tolsma John 
Published: February 2025

Objectives: Traditional pharmacokinetic/pharmacodynamic (PK/PD) and quantitative systems pharmacology (QSP) models often assume uniform drug distribution across various compartments, such as plasma and tissues [Shah and Betts, 2012; Jones et al., 2019], potentially overlooking critical spatial variations that impact drug efficacy and toxicity. This poster aims to:Highlight limitations: Present case studies demonstrating the critical influence of spatial drug distribution on therapeutic outcomes.Introduce a novel approach: Showcase an advanced modeling method that incorporates spatial heterogeneity into QSP frameworks. Demonstrate applications: Provide examples of this novel approach applied in real-world pharmacometric analyses. Methods: We utilized a Computational Fluid Dynamics (CFD) modeling approach [Reid 2021] to simulate the advection-diffusion processes of drug transport within complex tissue morphologies. This method provides a detailed spatial resolution of the pharmacokinetic (PK) profile, which is crucial for understanding how the drug distributes in targeted tissues. Additionally, we integrated these detailed CFD-generated PK profiles with pharmacodynamic (PD) models to evaluate the influence of spatial distribution on drug efficacy and toxicity. Results: We will present the modeling results from the following applications: Gene therapy delivery to CNS tissues: Achieving uniform vector genome transduction in the brain tissue via intraparenchymal delivery of adeno-associated virus (AAV) for gene therapy.Cell adhesion for anti-inflammatory treatments: Predicting leukocyte adhesion on endothelial surfaces, influenced by hydrodynamic flow profiles and the receptor-ligand binding interactions between leukocytes and endothelial cells.Transdermal patch: Analyzing the absorption kinetics and spatial drug distribution within the stratum corneum (SC), the primary barrier in transdermal drug delivery. Conclusions: Our findings highlight the substantial benefits of integrating Computational Fluid Dynamics (CFD) with traditional pharmacokinetic/pharmacodynamic (PK/PD) and quantitative systems pharmacology (QSP) models. This integration enhances the spatial resolution of drug distribution within target tissues, providing critical insights into drug efficacy and toxicity. The use of our CFD-enhanced PK/PD and QSP models (CFD-PK/PD and CFD-QSP) offers a more detailed understanding of drug behaviors in scenarios where the spatial distribution plays an important role, significantly improving therapeutic strategies and outcomes.Citations: [1] Jones, H.M., Z. Zhang, P. Jasper, H. Luo, L.B. Avery, L. E. King, H. Neubert, H. A. Barton, A.M. Betts and R. Webster, CPT Pharmacometrics Syst. Pharmacol. (2019) 8, 738–747.[2] Reid, L., “An Introduction to Biomedical Computational Fluid Dynamics.”, Adv. Exp. Med. Biol. (2021) 1334:205-222.[3] Shah, D.K. and A.M. Betts, J. Pharmacokinet. Pharmacodyn. (2012) 39:67–86.