2021.4.22 Fudan.pdf (19.33 MB)
Mechanism-Driven, Physiologically-Based Pharmacokinetic Modelling of Oral and Subcutaneous Administration
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.
History
Degree Type
- Doctor of Philosophy
Department
- PULSe (Life Sciences)
Campus location
- West Lafayette