TY  - JOUR
A1  - Scheer, Nico
A1  - Snaith, Mike
A1  - Wolf, C. Roland
A1  - Seibler, Jost
T1  - Generation and utility of genetically humanized mouse models
JF  - Drug Discovery Today
Y1  - 2013
U6  - http://dx.doi.org/10.1016/j.drudis.2013.07.007
SN  - 1359-6446
VL  - Vol 18
IS  - 23-24
SP  - 1200
EP  - 1211
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Wilson, Ian D.
A1  - Wilson, Claire E.
A1  - Scheer, Nico
A1  - Dickie, A.P.
A1  - Schreiter, K.
A1  - Wilson, E. M.
A1  - Riley, R. J.
A1  - Wehr, R.
A1  - Bial, J.
T1  - The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice
JF  - Biochemical pharmacology
Y1  - 2017
U6  - http://dx.doi.org/10.1016/j.bcp.2017.03.015
SN  - 1873-2968
VL  - Volume 135
SP  - 139
EP  - 150
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Zhang, Jin
A1  - Heimbach, Tycho
A1  - Scheer, Nico
A1  - Barve, Avantika
A1  - Li, Wenkui
A1  - Lin, Wen
A1  - He, Handan
T1  - Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4–Humanized Mouse Studies With PBPK Modeling
JF  - Journal of Pharmaceutical Sciences
N2  - 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.
Y1  - 2016
U6  - http://dx.doi.org/doi.org/10.1016/j.xphs.2016.01.021
SN  - 0022-3549
VL  - Volume 105
IS  - Issue 4
SP  - 1398
EP  - 1404
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Wilson, Ian D.
T1  - A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity
JF  - Drug Discovery Today
N2  - 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.
Y1  - 2016
U6  - http://dx.doi.org/10.1016/j.drudis.2015.09.002
SN  - 1359-6446
VL  - 21
IS  - 2
SP  - 250
EP  - 263
PB  - Elsevier
CY  - Amsterdam
ER  -