@article{ZhangHeimbachScheeretal.2016,
  author    = {Zhang, Jin and Heimbach, Tycho and Scheer, Nico and Barve, Avantika and Li, Wenkui and Lin, Wen and He, Handan},
  title     = {Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling},
  series = {Journal of Pharmaceutical Sciences},
  volume    = {Volume 105},
  journal   = {Journal of Pharmaceutical Sciences},
  number    = {Issue 4},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0022-3549},
  doi       = {doi.org/10.1016/j.xphs.2016.01.021},
  pages     = {1398 -- 1404},
  year      = {2016},
  abstract  = {NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.},
  language  = {en}
}
@incollection{WolfKapelyukhScheeretal.2015,
  author    = {Wolf, C. Roland and Kapelyukh, Yury and Scheer, Nico and Henderson, Colin J.},
  title     = {Application of Humanised and Other Transgenic Models to Predict Human Responses to Drugs},
  editor    = {Wilson, Alan G. E.},
  publisher = {RSC Publ.},
  address   = {Cambridge},
  isbn      = {978-1-78262-778-4},
  doi       = {10.1039/9781782622376-00152},
  pages     = {152 -- 176},
  year      = {2015},
  abstract  = {The use of transgenic animal models has transformed our knowledge of complex biochemical pathways in vivo. It has allowed disease processes to be modelled and used in the development of new disease prevention and treatment strategies. They can also be used to define cell- and tissue-specific pathways of gene regulation. A further major application is in the area of preclinical development where such models can be used to define pathways of chemical toxicity, and the pathways that regulate drug disposition. One major application of this approach is the humanisation of mice for the proteins that control drug metabolism and disposition. Such models can have numerous applications in the development of drugs and in their more sophisticated use in the clinic.},
  language  = {en}
}
@article{WilsonWilsonScheeretal.2017,
  author    = {Wilson, Ian D. and Wilson, Claire E. and Scheer, Nico and Dickie, A.P. and Schreiter, K. and Wilson, E. M. and Riley, R. J. and Wehr, R. and Bial, J.},
  title     = {The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice},
  series = {Biochemical pharmacology},
  volume    = {Volume 135},
  journal   = {Biochemical pharmacology},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {1873-2968},
  doi       = {10.1016/j.bcp.2017.03.015},
  pages     = {139 -- 150},
  year      = {2017},
  language  = {en}
}
@article{WilsonDickieSchreiteretal.2018,
  author    = {Wilson, C. E. and Dickie, A. P. and Schreiter, K. and Wehr, R. and Wilson, E. M. and Bial, J. and Scheer, Nico and Wilson, I. D. and Riley, R. J.},
  title     = {The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice},
  series = {Archives of Toxicology},
  volume    = {92},
  journal   = {Archives of Toxicology},
  number    = {6},
  publisher = {Springer},
  issn      = {1432-0738},
  doi       = {10.1007/s00204-018-2212-1},
  pages     = {1953 -- 1967},
  year      = {2018},
  abstract  = {The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.},
  language  = {en}
}
@article{StanleyHorsburghRossetal.2009,
  author    = {Stanley, Lesley A. and Horsburgh, Brian C. and Ross, Jillian and Scheer, Nico and Wolf, C. Roland},
  title     = {Drug transporters: Gatekeepers controlling access of xenobiotics to the cellular interior},
  series = {Drug Metabolism Reviews},
  volume    = {41},
  journal   = {Drug Metabolism Reviews},
  number    = {1},
  publisher = {Taylor \& Francis},
  address   = {London},
  issn      = {1097-9883},
  doi       = {10.1080/03602530802605040},
  pages     = {27 -- 65},
  year      = {2009},
  language  = {en}
}
@article{StanleyHorsburghRossetal.2006,
  author    = {Stanley, Lesley A. and Horsburgh, Brian C. and Ross, Jillian and Scheer, Nico and Wolf, C. Roland},
  title     = {Nuclear Receptors which play a pivotal role in drug disposition and chemical toxicity},
  series = {Drug Metabolism Reviews},
  volume    = {38},
  journal   = {Drug Metabolism Reviews},
  number    = {3},
  issn      = {1097-9883},
  doi       = {10.1080/03602530600786232},
  pages     = {515 -- 597},
  year      = {2006},
  language  = {en}
}
@article{ScheerWolf2014,
  author    = {Scheer, Nico and Wolf, C. Roland},
  title     = {Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications},
  series = {Xenobiotica},
  volume    = {44},
  journal   = {Xenobiotica},
  number    = {2},
  publisher = {Taylor \& Francis},
  address   = {Abingdon},
  issn      = {1366-5928},
  doi       = {10.3109/00498254.2013.815831},
  pages     = {96 -- 108},
  year      = {2014},
  abstract  = {1. Drug metabolizing enzymes and transporters play important roles in the absorption, metabolism, tissue distribution and excretion of various compounds and their metabolites and thus can significantly affect their efficacy and safety. Furthermore, they can be involved in drug-drug interactions which can result in adverse responses, life-threatening toxicity or impaired efficacy. Significant species differences in the interaction of compounds with drug metabolizing enzymes and transporters have been described. 2. In order to overcome the limitation of animal models in accurately predicting human responses, a large variety of mouse models humanized for drug metabolizing enzymes and to a lesser extent drug transporters have been created. 3. This review summarizes the literature describing these mouse models and their key applications in studying the role of drug metabolizing enzymes and transporters in drug bioavailability, tissue distribution, clearance and drug-drug interactions as well as in human metabolite testing and risk assessment. 4. Though such humanized mouse models have certain limitations, there is great potential for their use in basic research and for testing and development of new medicines. These limitations and future potentials will be discussed.},
  language  = {en}
}
@article{ScheerWolf2013,
  author    = {Scheer, Nico and Wolf, C. Roland},
  title     = {Xenobiotic receptor humanized mice and their utility},
  series = {Drug Metabolism Reviews},
  journal   = {Drug Metabolism Reviews},
  number    = {1},
  publisher = {Taylor \& Francis},
  address   = {London},
  issn      = {1097-9883},
  doi       = {10.3109/03602532.2012.738687},
  pages     = {110 -- 121},
  year      = {2013},
  language  = {en}
}
@article{ScheerWilson2016,
  author    = {Scheer, Nico and Wilson, Ian D.},
  title     = {A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity},
  series = {Drug Discovery Today},
  volume    = {21},
  journal   = {Drug Discovery Today},
  number    = {2},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {1359-6446},
  doi       = {10.1016/j.drudis.2015.09.002},
  pages     = {250 -- 263},
  year      = {2016},
  abstract  = {Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug-drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives.},
  language  = {en}
}
@article{ScheerSnaithWolfetal.2013,
  author    = {Scheer, Nico and Snaith, Mike and Wolf, C. Roland and Seibler, Jost},
  title     = {Generation and utility of genetically humanized mouse models},
  series = {Drug Discovery Today},
  volume    = {Vol 18},
  journal   = {Drug Discovery Today},
  number    = {23-24},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {1359-6446},
  doi       = {10.1016/j.drudis.2013.07.007},
  pages     = {1200 -- 1211},
  year      = {2013},
  language  = {en}
}