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AbstractA detailed introduction into the topic was obtained by developing a German-language online course named “Dose adjustment in Patients with Liver Disease” for the “Swiss Virtual Campus” in collaboration with PNN AG, a spin-off company of the ETH Zurich. This was followed by the German-language publication “Dosage Adaptation in Patients with Liver Disease” in “Grundlagen der Arzneimitteltherapie”, Documed, 2005, and an additional German-language online course for pharmacists named “Dose Adaptation of Drugs in Patients with Liver Insufficiency” published by PNN AG. The documents of these online courses and german publications can be found in the electronic appendix on CD-ROM. This extensive introduction into the topic was followed by the actual investigational thesis. The aim of the thesis was to define strategies for dose adaptation of drugs in patients with liver disease. The main focus was to compare the prediction of the kinetic behaviour as estimated using hepatic extraction with kinetic studies performed in patients with liver cirrhosis. For this purpose, the antineoplastic drugs and the central nervous agents on the market in Switzerland were studied. In chapter 2 and 3, a general introduction and recommendation of dosing in liver disease is given. Chapter 4 contains a more detailed description of the online course about dose adaptation in liver disease for the Swiss Virtual Campus. Chapter 6 contains the results of the literature research for kinetic studies in liver disease subdivided into the class of antineoplastic drugs (chapter 6.1) and psychotropic drugs (chapter 6.2). For each drug, the pharmacokinetic information was collected and drugs were classified according to their bioavailability / hepatic extraction in order to predict their kinetic behaviour in patients with decreased liver function as illustrated in chapter 3. These predictions were compared with kinetic studies in patients with liver disease. Furthermore, both the dose dependent and liver specific adverse reactions were listed, the identified kinetic studies in liver disease summarized for each drug and specific dosing recommendations given. In conclusion, there are currently not enough data for the safe use of cyctostatics and psychotropic drugs in patients with liver disease. There are obvious gaps about the kinetic behaviour of drugs in patients with liver disease, in particular concerning data about hepatic extraction and kinetic studies of drugs with biliary elimination in patients with cholestasis. Pharmaceutical companies should be urged to provide kinetic data (especially hepatic extraction) needed for the classification of such drugs. Kinetic studies should be conducted in patients with impaired liver function for drugs with primarily hepatic metabolism, allowing to give quantitative advise for dose adaptation.
Schlatter-Häner, Chantal. Dose adaptation of drugs in patients with liver disease. 2009, PhD Thesis, University of Basel, Faculty of Science.