2018
DOI: 10.1124/jpet.117.245712
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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

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Cited by 13 publications
(18 citation statements)
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“…A study by Kratochwil et al that combined data from active uptake, active efflux, and metabolic clearance, in the clearance assessment for a hepatitis B virus (HBV) candidate drug, illustrated how such data packages could be put together. 7 The simultaneous Figure 4. Induction of CYP3A4 enzyme activity in monocultured and micropatterned co-cultured hepatocytes.…”
Section: Consistent Multiple-parameter Measurementmentioning
confidence: 99%
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“…A study by Kratochwil et al that combined data from active uptake, active efflux, and metabolic clearance, in the clearance assessment for a hepatitis B virus (HBV) candidate drug, illustrated how such data packages could be put together. 7 The simultaneous Figure 4. Induction of CYP3A4 enzyme activity in monocultured and micropatterned co-cultured hepatocytes.…”
Section: Consistent Multiple-parameter Measurementmentioning
confidence: 99%
“…8,9,56 The aforementioned study of Kratochwil et al reported on measurements of metabolism, metabolite identification, and induction under high uptake conditions in a single test system to obtain consistent model inputs. 7 Furthermore, cellular activities in healthy and HBV-infected HepatoPac cultures were assessed, which raised the interesting possibility of simultaneously investigating in vitro PK and pharmacodynamics in a cellular model of hepatic disease and added to literature precedents for using co-cultured hepatocytes in this way. 7,57,58…”
Section: Parameter Crosstalkmentioning
confidence: 99%
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“…The involvement of active uptake in hepatic clearance can be flagged by the Extended Clearance Classification System, and in such cases measurements in hepatocyte models may be useful [34] and human clearance predictions may be improved with cross-species empirical scaling factors [35]. More advanced hepatocyte models are also being explored with respect to improved IVIVE for more complex cases [36][37][38]. Renal [39,40] and biliary [41] elimination involving active transport are also challenging to model mechanistically from in-vitro data, and, in general, prediction of human pharmacokinetics for transported molecules is difficult because absorption, distribution and elimination can all be affected [18].…”
Section: Metabolism and Eliminationmentioning
confidence: 99%
“…Measured activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4, UGT, and SULT for 30 days ) Diverse types of liver NPCs can be cultured in MPCCs without significantly affecting the homotypic interactions and polarity of hepatocytes on the micropatterned colonies Use nonliver fibroblasts for inducing optimal functions in hepatocytes Drug metabolite detection (Wang et al, 2010;Ballard et al, 2016) Drug clearance prediction (Chan et al, 2013;) DDIs including P450 induction and inhibition Kratochwil et al, 2018) Transporter, metabolism, and/or P450 induction interplay on drug disposition (Ramsden et al, 2014a;Moore et al, Engineered Liver Platforms for Drug Metabolism with the formation of bile canaliculi in advanced human liver platforms, the uptake and efflux of drugs and their metabolites via major transporters can be determined along with the interplay of drug transport with metabolism; indeed, the investigation of such an interplay embodies an important utility of advanced human liver platforms. Furthermore, whereas short-term (,4 days) P450 induction and inhibition via drugs can be carried out using conventional PHH monocultures, the most recent human liver models provide the ability to evaluate long-term (.7 days) P450 induction/inhibition and the coupling of such outcomes with drug clearance, metabolite formation, and toxicity assessments, as occurs in the clinic.…”
Section: Future Directions and Conclusionmentioning
confidence: 99%