PT  - JOURNAL ARTICLE
AU  - Nicole A. Kratochwil
AU  - Miriam Triyatni
AU  - Martina B. Mueller
AU  - Florian Klammers
AU  - Brian Leonard
AU  - Dan Turley
AU  - Josephine Schmaler
AU  - Aynur Ekiciler
AU  - Birgit Molitor
AU  - Isabelle Walter
AU  - Pierre-Alexis Gonsard
AU  - Charles A. Tournillac
AU  - Alexandre Durrwell
AU  - Michaela Marschmann
AU  - Russell Jones
AU  - Mohammed Ullah
AU  - Franziska Boess
AU  - Giorgio Ottaviani
AU  - Yuyan Jin
AU  - Neil J. Parrott
AU  - Stephen Fowler
TI  - 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
AID  - 10.1124/jpet.117.245712
DP  - 2018 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 237--248
VI  - 365
IP  - 2
4099  - http://jpet.aspetjournals.org/content/365/2/237.short
4100  - http://jpet.aspetjournals.org/content/365/2/237.full
SO  - J Pharmacol Exp Ther2018 May 01; 365
AB  - 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, and 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, such as hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for physiologically based pharmacokinetic (PBPK) modeling. The approach is exemplified in the case of (3S)-4-[[(4R)-4-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid RO6889678, a novel inhibitor of HBV with a complex absorption, distribution, metabolism, and excretion (ADME) profile. RO6889678 showed an intracellular enrichment of 78-fold in hepatocytes, with an apparent intrinsic clearance of 5.2 µl/min per mg protein and uptake and biliary clearances of 2.6 and 1.6 µl/min per mg protein, respectively. When apparent intrinsic clearance was incorporated into a PBPK model, the simulated oral human profiles were in good agreement with observed data at low doses but were underestimated at high doses due to unexpected overproportional increases in exposure with dose. In addition, the induction potential of RO6889678 on cytochrome P450 (P450) enzymes and transporters at steady state was assessed and cotreatment with ritonavir revealed a complex drug-drug interaction with concurrent P450 inhibition and moderate UDP-glucuronosyltransferase induction. Furthermore, we report on the first evaluation of in vitro pharmacokinetics studies using HBV-infected HepatoPac cocultures. Thus, long-term liver models have great potential as translational research tools exploring pharmacokinetics of novel drugs in vitro in health and disease.