Dose adaptation of drugs in patients with liver disease

A 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.