2021.4.22 Fudan.pdf (19.33 MB)
Mechanism-Driven, Physiologically-Based Pharmacokinetic Modelling of Oral and Subcutaneous Administration
thesisposted on 2021-04-23, 02:00 authored by Fudan ZhengFudan Zheng
Physiologically-based pharmacokinetic (PBPK) modeling is a mathematical tool to assess the adsorption, distribution, metabolism and excretion (ADME) process of drug inside the body. Drug absorption kinetics is commonly modeled using empirical compartment-based model, which hinders the interpretation of the role of formulation attributes on the in vivo fate of drug. This work elucidates the development and application of two mechanistic absorption models for: (i) oral delivery of small molecule; (ii) subcutaneous (SC) delivery of macromolecule. In the first part, PBPK model was employed to identify the potential reasons of severe bleeding when patients interchange brands of warfarin sodium tablets. The phase transition process was developed into the advanced compartmental absorption and transit (ACAT) model, which was coupled with population pharmacokinetic and pharmacodynamics (PKPD) model to explore the formulation impacts of warfarin sodium tablet on its therapeutic performance. Dissolution, precipitation, gastric transit and absorption kinetics of warfarin in gastrointestinal (GI) tract were well captured by the integrated model. The simulated PK and international normalized ratio (INR) are in line with clinical observations. Mean particle size and chiral ratio were identified as the critical attributes that may substantially increase hemorrhagic risks. In the second part, a multiphysics SC tissue model was implemented to account for tissue displacement, interstitial fluid flow and drug mass transport following SC injection. Spatiotemporal evolution of tissue deformation, porosity rise, pressure buildup and interstitial fluid velocity increase were observed during the injection stage of albumin. The simulated local absorption kinetics of albumin and IgG align well with the radiolabeled studies. Intrinsic tissue porosity, lymphatic vessel density, drug partition coefficient and hydraulic conductivity play important roles in local absorption process. The established SC absorption model was further integrated into the minimal PBPK (mPBPK) model to simulate drug transport from the injection site into the systemic distribution. The presystemic catabolism when drug transports through the posterior lymphatics was also modeled. Local absorption rate and presystemic clearance of therapeutic monoclonal antibodies (mAbs) were found to be correlated with the positive charge in the complementarity-determining region (CDR) and protein stability propensity, respectively. The abovementioned two PBPK platforms with mechanistic absorption models draw insights into predicting the impacts of physiochemical properties of drug molecule and physiological conditions of human population on the PKPD profiles.
- Doctor of Philosophy
- PULSe (Life Sciences)
- West Lafayette