Thesis
The importance of measured rat tissue partition coefficients in physiological based pharmacokinetic modelling : and the impact on human translational strategies in early drug discovery
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T17973
- Person Identifier (Local)
- 201593035
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Physiologically based pharmacokinetic (PBPK) modelling is an established in silico platform for simulating pharmacokinetics in pre-clinical species and humans, and is widely used within drug metabolism and pharmacokinetics (DMPK) research to facilitate the design of drug molecules with human pharmacokinetic profiles that lead to effective and safe therapeutic treatments. This research focuses on the mechanistic approaches used within PBPK models to parameterise drug distribution and how these methods influence plasma concentration-time (Cp) profiles. These in silico methodologies utilise properties of the drug and physiologies of the organism to predict tissue-to-plasma partition coefficients (Kp), which, when combined with regional blood flows, allow the movement of drug within the body to be modelled. In rat, these tissue Kp values can also be generated in vivo (Kp(meas)), where it is broadly recognised that incorporating these measured data into the species-specific models leads to improved pharmacokinetic simulations of both the Cp profile and the volume of distribution (Vss). Twenty-two novel compounds were selected for this research, covering a diverse range of GSK chemistries, including acidic, basic, neutral, and zwitterionic molecules. Following an investigation in rat, the standard GSK PBPK modelling approach incorporating predicted Kp values derived from the preferred Lukacova method demonstrated moderate to high levels of PK simulation accuracy for the vast majority (> 90 %) of basic, neutral, and zwitterionic compounds evaluated, with subsequent refinements to this methodology leading to enhanced model performance. However, this standard approach generally resulted in poorer simulation accuracy for the acidic compound class, which was attributed to the influence of transporter-mediated drug disposition among some of the stronger acids, and an apparent lack of sensitivity to reduced levels of ionisation as seen with the weaker acids. Incorporating Kp(meas) values led to varied improvements in rat PK simulations, which were dependent on compound class and the accuracy of the initial Kp predictions. The findings of this research formed the basis for an optimised modelling strategy that can be applied to specific compound classes, as shown with a clinical test-set, providing GSK and the wider modelling community with a robust set of go-to PBPK methodologies to predict human systemic pharmacokinetics early in drug discovery and support clinical dose projections.
- Advisor / supervisor
- Mottram, Nigel
- Scott-Stevens, Paul
- Resource Type
- Note
- Previously held under moratorium in the Chemistry Department (GSK) from 27 March 2024 until 24 April 2026.
- DOI
- Funder
- Embargo Note