Donzelli, Massimiliano. Development, validation and application of the Basel phenotyping cocktail. 2015, PhD Thesis, University of Basel, Faculty of Science.
Available under License CC BY-NC-ND (Attribution-NonCommercial-NoDerivatives).
Official URL: http://edoc.unibas.ch/diss/DissB_11522
In this dissertation we describe the development of a new phenotyping cocktail (Basel cocktail) containing caffeine, efavirenz, losartan, omeprazole, metoprolol, and midazolam as probe drugs for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, respectively. We validated the new phenotyping procedure in two clinical studies in healthy volunteers: the Basel cocktail studies I and II. With the data acquired in study I, the absence of mutual interactions between the new combinations of probe drugs selected for the Basel phenotyping cocktail was established. Furthermore we showed that evaluation of the metabolic ratios in plasma at single time-points can replace conventional full AUC measurements. Additionally, the use of dried blood spots (DBS) and saliva as minimally or non-invasive sampling collection procedures were explored.
For a comprehensive evaluation of the new phenotyping cocktail, the influence of genetic factors or co-administration of an enzyme inducer or inhibitor on the metabolic ratios of the Basel cocktail had to be assessed. The Basel cocktail study II was performed to characterize the range of the chosen phenotyping metrics under conditions of induction and inhibition. Additionally we measured the metabolic ratios in saliva and DBS.
Bioanalysis and genotype determination were key tools for this project. We developed and validated bioanalytical methods for simultaneous detection of probe drugs and their main metabolites in different human matrices. To maintain clinical applicability, short return times were required. Therefore highly sensitive bioanalytical methods with simple sample work-up and short run-times were developed. Study subjects providing consent were genotyped for the most relevant single-nucleotide polymorphisms and when possible correlations between genotype and phenotype were assessed.
In the Basel cocktail studies I and II, the lowest commercially available doses and formulations of the phenotyping drugs were used. To simplify probe drug administration, a prototype of a combi-pill containing all six cocktail probe drugs was developed and tested in a single subject in a clinical pilot study. Pharmacokinetic profiles of the new formulation were comparable with the ones obtained after intake of the individual probe drugs in the commercial formulations. This new cocktail combi-pill will be formally evaluated in a clinical study (Basel cocktail study III) in healthy volunteers.
The use of phenotyping information to personalize cancer therapy with tyrosine kinase inhibitors is under investigation in an ongoing clinical trial. Individual CYP3A4 and CYP1A2 phenotype will be assessed using probe drugs of the Basel cocktail and the correlation of the phenotyping metrics with sunitinib, pazopanib or erlotinib exposure will be analyzed.
Taken together the work performed during this dissertation was important to improve the clinical applicability of phenotyping, which is essential to move this important tool for personalized medicine closer to the clinical routine.
|Committee Members:||Krähenbühl, Stephan and Huwyler, Jörg|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||153 S.|
|Last Modified:||30 Jun 2016 10:58|
|Deposited On:||18 Nov 2015 15:34|
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