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Simultaneous Assessment of Clearance, Metabolism, Induction and Drug-Drug Interaction Potential using a Long-Term In Vitro Liver Model for a Novel Hepatitis B Virus Inhibitor.

Simultaneous Assessment of Clearance, Metabolism, Induction and Drug-Drug Interaction Potential using a Long-Term In Vitro Liver Model for a Novel Hepatitis B Virus Inhibitor.
Author Information (click to view)

Kratochwil NA, Triyatni M, Mueller MB, Klammers F, Leonard B, Turley D, Schmaler J, Ekiciler A, Molitor B, Walter I, Gonsard PA, Tournillac CA, Durrwell A, Marschmann M, Jones R, Ullah M, Boess F, Ottaviani G, Yin Y, Parrott NJ, Fowler S,


Kratochwil NA, Triyatni M, Mueller MB, Klammers F, Leonard B, Turley D, Schmaler J, Ekiciler A, Molitor B, Walter I, Gonsard PA, Tournillac CA, Durrwell A, Marschmann M, Jones R, Ullah M, Boess F, Ottaviani G, Yin Y, Parrott NJ, Fowler S, (click to view)

Kratochwil NA, Triyatni M, Mueller MB, Klammers F, Leonard B, Turley D, Schmaler J, Ekiciler A, Molitor B, Walter I, Gonsard PA, Tournillac CA, Durrwell A, Marschmann M, Jones R, Ullah M, Boess F, Ottaviani G, Yin Y, Parrott NJ, Fowler S,

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The Journal of pharmacology and experimental therapeutics 2018 02 16() pii jpet.117.245712
Abstract

Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross species metabolism, comparison of low clearance drugs as well as induction studies. Here, we present studies using a long-term liver model which show how metabolism and active transport, drug-drug interactions and enzyme induction in healthy and diseased states, e.g. hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for PBPK modeling. The approach is exemplified in the case of RO6889678, a novel inhibitor of HBV with a complex ADME profile. RO6889678 showed an intracellular enrichment of 78-fold in hepatocytes with an apparent intrinsic clearance of 5.2 μL minmgprotein and uptake and biliary clearances of 2.6 and 1.6 μL minmgprotein, respectively. When apparent intrinsic clearance was incorporated into a physiologically based pharmacokinetic model the simulated oral human profiles were in good agreement with observed data at low doses, but were under estimated at high doses due to unexpected over proportional increases in exposure with dose. In addition, the induction potential of RO6889678 on CYP enzymes and transporters at steady state was assessed and co-treatment with ritonavir revealed a complex DDI with concurrent CYP inhibition and moderate UGT induction. Furthermore, we report on the first evaluation of in vitro pharmacokinetics studies using HBV-infected HepatoPacco-cultures. Thus, long-term liver models have great potential as translational research tools exploring pharmacokinetics of novel drugs in vitro in health and disease.

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