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 humans and pre-clinical species. These models are widely used within drug metabolism and pharmacokinetic (DMPK) research to facilitate the design of drug molecules with human pharmacokinetic (PK) profiles that lead to effective and safe therapeutic treatments. This research focuses on the mechanistic approaches within PBPK models to parameterise drug distribution, and their influence on plasma concentration-time (Cp) profiles. As such, 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 allows the movement of drug within the body to be modelled. However, Kp values can also be generated in vivo, where it is generally accepted that these measured values (Kp(meas)) lead to improved pharmacokinetic simulations with respect to both the accuracy of the Cp profile and mechanistic estimates of the volume of distribution. Twenty-two novel compounds were identified for this research covering a diverse range of GSK chemistries; including, acidic, basic, neutral and zwitterionic compounds. Overall, the standard GSK PBPK modelling approach, incorporating in silico Kp values derived from the preferred Lukacova method, demonstrated moderate to high levels of PK simulation accuracy in the rat for the majority of compounds across these classes (> 90 % for basic, neutral and zwitterionic molecules); however, refinements to these methodologies were proposed leading to greater model performance. Conversely, the Lukacova PBPK methodology showed varied levels of simulation accuracy (poor to high) in the rat for the acidic compound class which was attributed to the influence of transporter mediated drug disposition (TMDD), and the apparent lack of sensitivity to reduced acidic strength. Incorporating rat Kp(meas) values showed varying levels of improvements to model performance, which was dependent upon compound class, and the accuracy of the initial Kp predictions. These observations provided the foundation for an optimised modelling strategy that could be applied to specific compounds classes, affording GSK and the wider modelling community with a robust set of go-to PBPK methodologies that can be applied early in drug discovery to predict systemic pharmacokinetics in human 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.
  • The confidentiality statement on each page of this thesis DOES NOT apply.
DOI
Funder
Embargo Note
  • This thesis is restricted to Strathclyde users only until 27 March 2029.

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