In Silico Modeling for the Prediction of Dose and Pathway-Related Adverse Effects in Humans From In Vitro Repeated-Dose Studies

Sebastian Klein, Silvia Maggioni, Joachim Bucher, Daniel Mueller, Jens Niklas, Valery Shevchenko, Klaus Mauch, Elmar Heinzle, Fozia Noor*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Long-term repeated-dose toxicity is mainly assessed in animals despite poor concordance of animal data with human toxicity. Nowadays advanced human in vitro systems, eg, metabolically competent HepaRG cells, are used for toxicity screening. Extrapolation of in vitro toxicity to in vivo effects is possible by reverse dosimetry using pharmacokinetic modeling. We assessed long-term repeated-dose toxicity of bosentan and valproic acid (VPA) in HepaRG cells under serum-free conditions. Upon 28-day exposure, the EC50 values for bosentan and VPA decreased by 21-and 33-fold, respectively. Using EC10 as lowest threshold of toxicity in vitro, we estimated the oral equivalent doses for both test compounds using a simplified pharmacokinetic model for the extrapolation of in vitro toxicity to in vivo effect. The model predicts that bosentan is safe at the considered dose under the assumed conditions upon 4 weeks exposure. For VPA, hepatotoxicity is predicted for 4% and 47% of the virtual population at the maximum recommended daily dose after 3 and 4 weeks of exposure, respectively. We also investigated the changes in the central carbon metabolism of HepaRG cells exposed to orally bioavailable concentrations of both drugs. These concentrations are below the 28-day EC10 and induce significant changes especially in glucose metabolism and urea production. These metabolic changes may have a pronounced impact in susceptible patients such as those with compromised liver function and urea cycle deficiency leading to idiosyncratic toxicity. We show that the combination of modeling based on in vitro repeated-dose data and metabolic changes allows the prediction of human relevant in vivo toxicity with mechanistic insights.

Original languageEnglish
Pages (from-to)55-66
Number of pages12
JournalToxicological Sciences
Volume149
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016
Externally publishedYes

Keywords

  • Bosentan
  • HepaRG
  • IVIVE
  • metabolic pathway
  • Oral equivalent dose
  • repeated-dose toxicity
  • reverse dosimetry
  • VPA

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