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In vitro to in vivo extrapolation of valproic acid hepatotoxicity: A biokinetic and physiologically based toxicokinetic informed approach

: Fisher, C.P.; Hatley, O.; Vugt, B. van; Bois, F.; Escher, Sylvia E.; Gardner, Iain


Toxicology letters 295 (2018), Supplement 1, pp.S246, Abstract P24-03
ISSN: 0378-4274
ISSN: 1879-3169
European Societies of Toxicology (EUROTOX Congress) <54, 2018, Brussels>
Fraunhofer ITEM ()

Valproic acid (VPA) is used in the management of seizures, bipolar disorder, and migraines however, its use is associated with a number of adverse effects including hepatic steatosis. Whole-body physiologically based toxicokinetic (PBTK) models were developed to simulate the tissue concentrations of VPA in the rat and human. The models were parameterised using physicochemical properties and reverse translation approaches from published data. In order to recover the extended systemic exposure observed in rodent pre-clinical studies, it was necessary to incorporate the enterohepatic recirculation resultant from deconjugation of biliary cleared glucoronidated metabolites in the gut, and the subsequent reabsorption of parent compound. In vitro reporter assays showed activation of the pregnane X receptor (PXR) and peroxisome proliferator activated receptor alpha (PPARa) in response to VPA exposure; both previously identified as molecular initiating events (MIEs) in the hepatic steatosis adverse outcome pathway. Using a steady-state biokinetic model of in vitro distribution, nominal VPA treatment concentrations identified as activating PXR and PPARa in vitro were used to predict the corresponding intracellular concentrations. Using the verified rat and human PBTK models, a reverse-dosimetry approach was employed to determine the oral dose resulting in maximal hepatic concentrations corresponding to the intracellular concentration associated with activating these MIEs in vitro. Doses of 3.7 mg/kg and 1.7 mg/kg in rat and human, respectively, were determined to result in hepatic concentrations associated with activation of MIEs in the steatosis AOP. As might be expected, the MIE activating dose determined in rat, was more than two orders of magnitude lower than the oral LOAEL identified in rat repeat dose toxicity studies (500mg/kg) linked with histopathological scoring of hepatic steatosis. However, the MIE activating dose in humans, equivalent to ∼125mg, is well within the therapeutic dosing range. Repeat dosing at therapeutic levels could result in sustained activation of MIEs associated with adverse hepatic outcomes. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 681002.