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

Kratochwil, Nicole A.; Triyatni, Miriam; Mueller, Martina B.; Klammers, Florian; Leonard, Brian C.; Turley, Dan; Schmaler, Josephine; Ekiciler, Aynur; Molitor, Birgit; Walter, Isabelle; Gonsard, Pierre-Alexis; Tournillac, Charles A.; Durrwell, Alexandre; Marschmann, Michaela; Jones, Russell G.; Ullah, Mohammed; Boess, Franziska; Ottaviani, Giorgio; Jin, Yuyan; Parrott, Neil; Fowler, Stephen

doi:10.1124/jpet.117.245712

Cited by 13 publications

(18 citation statements)

References 45 publications

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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%

“…5 Recent developments have shown that advanced 2D hepatocyte co-culture systems (in which hepatocytes are cultivated together with supportive nonparenchymal cells) may be applied to many of these processes and, more interestingly, to the study of the combination of multiple processes to overall drug metabolism. 6,7 Following on from interesting proof-of-concept studies, [8][9][10] such advanced cellular model systems need now to be placed within the palette of tools used in routine drug development and show consistent added value in the optimization and selection of drug candidates, especially in consideration of limitedthroughput capability and cost.…”

Section: Introductionmentioning

confidence: 99%

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Application of New Cellular and Microphysiological Systems to Drug Metabolism Optimization and Their Positioning Respective to In Silico Tools

et al. 2019

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New cellular model systems for drug metabolism applications, such as advanced 2D liver co-cultures, spheroids, and microphysiological systems (MPSs), offer exciting opportunities to reproduce human biology more closely in vitro with the aim of improving predictions of pharmacokinetics, drug–drug interactions, and efficacy. These advanced cellular systems have quickly become established for human intrinsic clearance determination and have been validated for several other absorption, distribution, metabolism, and excretion (ADME) applications. Adoption will be driven through the demonstration of clear added value, for instance, by more accurate and precise clearance predictions and by more reliable extrapolation of drug interaction potential leading to faster progression to pivotal proof-of-concept studies. New experimental systems are attractive when they can (1) increase experimental capacity, removing optimization bottlenecks; (2) improve measurement quality of ADME properties that impact pharmacokinetics; and (3) enable measurements to be made that were not previously possible, reducing risk in ADME prediction and candidate selection. As new systems become established, they will find their place in the repository of tools used at different stages of the research and development process, depending on the balance of value, throughput, and cost. In this article, we give a perspective on the integration of these new methodologies into ADME optimization during drug discovery, and the likely applications and impacts on drug development.

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Section: Consistent Multiple-parameter Measurementmentioning

confidence: 99%

Section: Parameter Crosstalkmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Application of New Cellular and Microphysiological Systems to Drug Metabolism Optimization and Their Positioning Respective to In Silico Tools

et al. 2019

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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%

Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies

et al. 2019

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Physiologically based pharmacokinetic modelling is well established in the pharmaceutical industry and is accepted by regulatory agencies for the prediction of drug-drug interactions. However, physiologically based pharmacokinetic modelling is valuable to address a much wider range of pharmaceutical applications, and new regulatory impact is expected as its full power is leveraged. As one example, physiologically based pharmacokinetic modelling is already routinely used during drug discovery for in-vitro to in-vivo translation and pharmacokinetic modelling in preclinical species, and this leads to the application of verified models for first-inhuman pharmacokinetic predictions. A consistent cross-industry strategy in this application area would increase confidence in the approach and facilitate further learning. With this in mind, this article aims to enhance a previously published first-inhuman physiologically based pharmacokinetic model-building strategy. Based on the experience of scientists from multiple companies participating in the GastroPlus™ User Group Steering Committee, new Absorption, Distribution, Metabolism and Excretion knowledge is integrated and decision trees proposed for each essential component of a first-inhuman prediction. We have reviewed many relevant scientific publications to identify new findings and highlight gaps that need to be addressed. Finally, four industry case studies for more challenging compounds illustrate and highlight key components of the strategy.

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“…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%

Advances in Engineered Human Liver Platforms for Drug Metabolism Studies

Underhill

Khetani

2018

Drug Metab Dispos

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Metabolism in the liver often determines the overall clearance rates of many pharmaceuticals. Furthermore, induction or inhibition of the liver drug metabolism enzymes by perpetrator drugs can influence the metabolism of victim drugs (drug-drug interactions). Therefore, determining liver-drug interactions is critical during preclinical drug development. Unfortunately, studies in animals are often of limited value because of significant differences in the metabolic pathways of the liver across different species. To mitigate such limitations, the pharmaceutical industry uses a continuum of human liver models, ranging from microsomes to transfected cell lines and cultures of primary human hepatocytes (PHHs). Of these models, PHHs provide a balance of high-throughput testing capabilities together with a physiologically relevant cell type that exhibits all the characteristic enzymes, cofactors, and transporters. However, PHH monocultures display a rapid decline in metabolic capacity. Consequently, bioengineers have developed several tools, such as cellular microarrays, micropatterned cocultures, self-assembled and bioprinted spheroids, and perfusion devices, to enhance and stabilize PHH functions for ≥2 weeks. Many of these platforms have been validated for drug studies, whereas some have been adapted to include liver nonparenchymal cells that can influence hepatic drug metabolism in health and disease. Here, we focus on the design features of such platforms and their representative drug metabolism validation datasets, while discussing emerging trends. Overall, the use of engineered human liver platforms in the pharmaceutical industry has been steadily rising over the last 10 years, and we anticipate that these platforms will become an integral part of drug development with continued commercialization and validation for routine screening use.

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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

Cited by 13 publications

References 45 publications

Application of New Cellular and Microphysiological Systems to Drug Metabolism Optimization and Their Positioning Respective to In Silico Tools

Application of New Cellular and Microphysiological Systems to Drug Metabolism Optimization and Their Positioning Respective to In Silico Tools

Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies

Advances in Engineered Human Liver Platforms for Drug Metabolism Studies

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