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Hierarchical mechanistic modelling of clinical pharmacokinetic data

Wendling, Thierry

[Thesis]. Manchester, UK: The University of Manchester; 2016.

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Abstract

Pharmacokinetic and pharmacodynamic models can be applied to clinical study data using various modelling approaches depending on the aim of the analysis. In population pharmacokinetics for instance, simple compartmental models can be employed to describe concentration-time data, identify prognostic factors and interpolate within well-defined experimental conditions. The first objective of this thesis was to illustrate such a ‘semi-mechanistic’ pharmacokinetic modelling approach using mavoglurant as an example of a compound under clinical development. In particular, methods to accurately characterise complex oral pharmacokinetic profiles and evaluate the impact of absorption factors were investigated.When the purpose of the model-based analysis is to further extrapolate beyond the experimental conditions in order to guide the design of subsequent clinical trials, physiologically-based pharmacokinetic (PBPK) models are more valuable as they incorporate information not only on the drug but also on the system, i.e. on mammillary anatomy and physiology. The combination of such mechanistic models with statistical modelling techniques in order to analysis clinical data has been widely applied in toxicokinetics but has only recently received increasing interest in pharmacokinetics. This is probably because, due to the higher complexity of PBPK models compared to conventional pharmacokinetic models, additional efforts are required for adequate population data analysis. Hence, the second objective of this thesis was to explore methods to allow the application of PBPK models to clinical study data, such as the Bayesian approach or model order reduction techniques, and propose a general mechanistic modelling workflow for population data analysis. In pharmacodynamics, mechanistic modelling of clinical data is even less common than in pharmacokinetics. This is probably because our understanding of the interaction between therapeutic drugs and biological processes is limited and also because the types of data to analyse are often more complex than pharmacokinetic data. In oncology for instance, the most widely used clinical endpoint to evaluate the benefit of an experimental treatment is survival of patients. Survival data are typically censored due to logistic constraints associated with patient follow-up. Hence, the analysis of survival data requires specific statistical techniques. Longitudinal tumour size data have been increasingly used to assess treatment response for solid tumours. In particular, the survival prognostic value of measures derived from such data has been recently evaluated for various types of cancer although not for pancreatic cancer. The last objective of this thesis was therefore to investigate different modelling approaches to analyse survival data of pancreatic cancer patients treated with gemcitabine, and compare tumour burden measures with other patient clinical characteristics and established risk factors, in terms of predictive value for survival.