Pharmacogenomics in drug development : implementation and application of PKPD model based approaches

Leiden Repository

Pharmacogenomics in drug development : implementation and application of PKPD model based approaches

Title: Pharmacogenomics in drug development : implementation and application of PKPD model based approaches
Author: Stringer, Frances
Publisher: Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
Issue Date: 2015-01-13
Keywords: Clinical pharmacology
Drug development
Pharmacogenetics
Diabetes
Genotype
Population approach
NONMEM
Abstract: Model based approaches, integrating physiological parameters or linking exposure with response, are powerful tools to quantify and evaluate the impact of genetic differences that are reflected as variability of drug exposure and/or clinical response(s). This thesis “Pharmacogenomics in Drug Development: Implementation and Application of PKPD Model Based Approaches” focused on genotype differences in explaining inter-individual variability in drug metabolism and clinical response. Population pharmacokinetic and pharmacodynamic models were developed to evaluate the relationship between exposure differences resulting from UGT2B15 genotype and their effects on both fasting plasma glucose and glycosylated haemoglobin for the type 2 diabetes drug, Sipoglitazar™. The model was used to quantify the optimal dose and regime (Single treatment/genotyped-based or titrated based upon response) for future clinical trials. Evaluating the potential impact of genetic differences early during development is important to appropriately design future clinical studies and to ensure that exposure response relationships for efficacy and safety can be identifed for all genetic subgroups. Ultimately, these model-based approaches can be used to determine if covariate-based dose individualization would be advantageous/beneficial to normalize exposure and minimize variability in clinical outcomes across heterogeneous clinical populations.
Description: Promotor: M. Danhof, Co-Promotor: J. de Jongh
With Summary in Dutch
Faculty: Faculteit der Wiskunde en Natuurwetenschappen
Citation: Stringer, F., 2015, Doctoral Thesis, Leiden University
Sponsor: Takeda Pharmaceutical Company
Handle: http://hdl.handle.net/1887/31601
 

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