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  - Dallas, Shannon
A1  - Salphati, Laurent
A1  - Gomez-Zepeda, David
A1  - Wanek, Thomas
A1  - Chen, Liangfu
A1  - Chu, Xiaoyan
A1  - Kunta, Jeevan
A1  - Mezler, Mario
A1  - Menet, Marie-Claude
A1  - Chasseigneaux, Stephanie
A1  - Declèves, Xavier
A1  - Langer, Oliver
A1  - Pierre, Esaie
A1  - DiLoreto, Karen
A1  - Hoft, Carolin
A1  - Laplanche, Loic
A1  - Pang, Jodie
A1  - Pereira, Tony
A1  - Andonian, Clara
A1  - Simic, Damir
A1  - Rode, Anja
A1  - Yabut, Jocelyn
A1  - Zhang, Xiaolin
A1  - Scheer, Nico
T1  - Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model
JF  - Molecular Pharmacology
N2  - Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp−/−) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.
Y1  - 2016
U6  - http://dx.doi.org/10.1124/mol.115.102079
SN  - 1521-0111
VL  - 89
IS  - 5
SP  - 492
EP  - 504
PB  - ASPET
CY  - Bethesda, Md.
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  -