Poster 60 - SBMC2018 - Improved evaluation of caffeine-based dynamical liver function tests by accounting for lifestyle and pharmacological modifiers like smoking and oral contraceptive use

Improved evaluation of caffeine-based dynamical liver function tests by accounting for lifestyle and pharmacological modifiers like smoking and oral contraceptive use

Matthias König1,*, Ute Hofmann2, Jan Grzegorzewski1, Reinhold Kerb2, Svitlana Igel2, Elke Schäffeler2 and Matthias Schwab2,3

1Institute for Theoretical Biology, Institute of Biology, Humboldt University, Berlin, Germany, koenigmx@hu-berlin.de, orcid.org/0000-0003-1725-179X 2Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, Ute.Hofmann@ikp-stuttgart.de 3Department of Clinical Pharmacology, University Hospital, Tübingen, Germany, Matthias.Schwab@ikp-stuttgart.de *Corresponding/Presenting author

Quantitative dynamical liver function tests evaluate the function of the liver via the clearance of a given test substance, thereby providing in vivo information on the metabolic capacity of the liver. The liver function test based on caffeine is known for long, but its clinical usability is hampered by large interindividual variability and dose-dependency. In this work we developed a detailed physiologically based pharmacokinetics model (PBPK) for the evaluation of the caffeine clearance test, assessing hepatic conversion of caffeine to paraxanthine via cytochrome P450 CYP1A2. The model is able to reproduce results from a wide range of reported studies under varying caffeine doses and application routes. The model accounts for interindividual differences based on distributions of CYP1A2 and modification of CYP1A2 activity via lifestyle factors, e.g. smoking, and pharmacological interactions, e.g. oral contraceptives. Validation was performed with an independent clinical trial (EudraCT 2011-002291-16, ClinicalTrials.gov NCT01788254) demonstrating an improved prediction using individualized models accounting for smoking status and contraceptive use. Hereby, we could reduce the large variability in the test results providing the basis for better sensitivity and specificity in diagnosing subjects with liver problems.