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Lin, Louis

University of British Columbia

Predicting the human pharmacokinetics (PK) is a crucial step for rational decision making in the search for new medicines. However, this can be difficult, especially for orally administered compounds. An emerging mathematical tool is physiologically-based pharmacokinetic (PBPK) modeling, which integrates physiology with the physicochemical properties of a compound to simulate a concentration-time profile. This powerful tool is complex and most commonly applied in later stages of development, whereas early-stage modeling generally consists of empirical models such as the one-compartment model. In this thesis we assess a PBPK modeling approach for prospective predictions using vismodegib (Erivedge®) as a model drug. Vismodegib is a poorly soluble drug, similar to many compounds currently in development, with unanticipated nonlinear PK behavior in humans. For a 150 mg oral dose, accumulation was roughly 5-fold lower than expected and steady-state was reached in 7-14 days, rather than the 60 days predicted under linear PK assumptions. Furthermore, the 150 mg, 270 mg, and 540 mg dose cohorts in clinical trials displayed similar exposure at steady-state. Here we show that an oral PBPK model, custom built with limited data and validated in the rat, dog, and monkey, can outperform one-compartment models in predicting human PK. A plasma protein binding model was then built using in vitro data and embedded into the PBPK model. This refined PBPK model was then used to demonstrate how these powerful tools can evaluate mechanisms driving nonlinear PK, specifically nonsink permeation and saturable binding to alpha-1-acid glycoprotein (AAG). The model was used to demonstrate how nonsink permeation plays a significant role in the absorption profile, driven by its low solubility and low clearance. We introduce a new parameter, the permeation gradient factor (PGF), as a metric to measure the influence of nonsink permeation on absorption. The contributions of nonsink permeation and saturable AAG binding to the nonlinear PK of vismodegib are then quantitatively evaluated using the oral PBPK model. Overall, the work in this thesis provides a case study to illustrate the value of early application of PBPK models for predicting and examining mechanisms impacting the PK of a potential drug.

Text

2024-07-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83448

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/