Application of phenotyping and therapeutic drug monitoring in personalised drug treatment : Peter Benjamin Berger aus Basel, Basel-Stadt

Berger, Benjamin. Application of phenotyping and therapeutic drug monitoring in personalised drug treatment : Peter Benjamin Berger aus Basel, Basel-Stadt. 2016, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12147

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As every individual is a product of his/her genes and environment, which can be regarded as a paraphrase of an individual’s phenotypic characteristic, it becomes apparent as to why the concept of personalised medicine, i.e. tailoring a treatment regimen to an individual’s needs, remains an ever-prevalent topic in the medical community. Human cytochrome P450 enzymes (CYPs) are accountable for the oxidative metabolism of approximately 50% of commonly used drugs as well as endogenous compounds. However, CYP activity is exceedingly variable amongst individuals. Over the course of my PhD project, I worked on five different projects that implicated the utility of two valuable tools in personalised medicine: namely, phenotyping and therapeutic drug monitoring. The determination of a person’s enzymatic activity through phenotyping can help guide a GP’s effort to personalise drug therapy by administering the applicable dose, thereby improving efficacy and reducing side effects at the start of therapy. Therapeutic drug monitoring (TDM) on the other hand, enables the continued observation of a patient’s drug concentration, predominantly in plasma, thus allowing patients that are at risk of either over-/ or underdosing to be identified. In the past two decades, many different in vivo phenotyping cocktails, enabling the simultaneous assessment of multiple CYP isoforms, e.g. Cooperstown- [1], Inje- [2], Quebec- [3], Karolinska- [4], and the Pittsburgh-cocktail [5], as well as a great number of in vitro cocktails [6-14] were developed. Metabolism studies performed in vitro are useful to the extent of acquiring anticipatory information of in vivo predictions of CYP- inhibition/ -induction in an efficient time and cost saving manner. It is, however, uncommon to use established in vivo cocktails for in vitro studies [7]. Nevertheless, using probe substrates previously unaccustomed to in vitro cocktail studies, e.g. efavirenz (CYP2B6), losartan (CYP2C9), and metoprolol (CYP2D6), we were able to show the potential of the Basel cocktail [15, 16] to characterise a variety of different liver cell models. Of particular interest to our study was the characterisation of 3D primary human hepatocytes (PHH), co-cultured with 3T3-mouse fibroblasts [17]. By using the same batch of PHH in 2D and 3D-culture, we were able to show the functional benefits of a co-culture system, enabling hepatocytes to reside in a 3D environment, and leading to improved CYP activity and mRNA expression. In subsequent studies, we were able to provide explanations for pending in vivo observations [15], through combining knowledge of freshly acquired in vitro and in vivo characterisation data of the Basel cocktail. In the second study, we demonstrated that the α-hydroxymetoprolol formation is not mediated solely by CYP2D6, since under induced conditions and through experiments in isoform specific supersomes, the involvement of CYP3A4 also became apparent. This does not, however, impede the continued applicability of metoprolol as probe substrate of CYP2D6 since the involvement of CYP3A4 only becomes apparent when induction is evaluated, which is commonly not done for CYP2D6. In the third study, we were able to show, through an in vitro interactions study, that flurbiprofen can be used to replace losartan as a phenotyping drug for CYP2C9. Subsequently, a pilot study (n=2) showed the prospect of simplifying the cocktail administration through the use of a combi-capsule containing all six probe drugs of the modified Basel cocktail. After having previously tested the phenotyping capacities of the Basel cocktail in two studies involving young, healthy, male volunteers [15, 16], the fourth study of this thesis demonstrates that we successfully used caffeine (CYP1A2) and midazolam (CYP3A4) to phenotype elderly, patients of both sexes that were being treated for non-small cell lung cancer (NSCLC) with erlotinib (Tarceva®). In so doing, we were able to show that subjects with a slow CYP3A4 metabolism had a higher likelihood of developing cutaneous toxicity than patients with an extensive metabolism. While the fourth study touched upon the possible usefulness of collecting DBS with which to perform TDM, as opposed to conventional plasma samples, the fifth and final study was devoted entirely to this topic. Here, we demonstrated the development, validation, and application of an automated DBS extraction method, while incorporating an evaluation of an antiretroviral adherence/ therapeutic drug monitoring study. Our study was able to show that concentrations of two antiretroviral drugs, nevirapine and efavirenz, could reliably be determined by automated extraction in DBS samples that had been obtained in a challenging setting in rural Tanzania.
Advisors:Krähenbühl, Stephan and Huwyler, Jürg
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12147
Thesis status:Complete
Number of Pages:1 Online-Ressource (IV, 170 Seiten)
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Last Modified:08 Feb 2020 14:37
Deposited On:18 May 2017 08:10

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