Trends in Pharmacological Sciences
OpinionCan ‘humanized’ mice improve drug development in the 21st century?
Section snippets
Modeling human drug metabolism and drug response
As time, cost, and regulatory hurdles for testing new drug candidates in human subjects have increased, a greater emphasis has been placed on developing preclinical methodologies that provide more predictive information about human drug metabolism or pharmacodynamic responses. Interspecies differences in drug metabolism create qualitative and quantitative differences between drug metabolites produced in humans and animal species. As a consequence, the results obtained from in vitro systems and
Different engineering leads to different performance
When considering their utility for drug development, it is important to recognize that chimeric mice with different genetically engineered modifications will have intrinsically different properties. Based on genetic engineering modifications that confer immunodeficiency and cause damage to endogenous murine liver cells, there are three different types of chimeric mouse models (Table 1). Chimeric mice were first generated by Brinster and colleagues in 1991 when a transgene with an albumin
Areas of opportunity for 21st century drug development
At present, there are no regulatory requirements for using chimeric mouse data, nor does any pharmaceutical company routinely use chimeric mice to evaluate candidate medications prior to human clinical studies. Nevertheless, given the high failure rate of new compounds, using chimeric mice to characterize drug candidates could improve many traditional and newly emerging problem areas for drug development. One traditional problem is that existing in vitro systems and in vivo animal testing
Moving forward
Because the liver is affected by many drug-induced toxicities, toxicology studies in chimeric mice could have a large impact on drug development. However, we do not yet have definitive examples of drug-induced toxicities that were detected in chimeric mice but not in conventional rodent models. Analysis of acetaminophen-induced liver toxicity in chimeric uPA/SCID mice demonstrated that murine and human liver cells were differentially susceptible to this toxicity [34]. Although this provides
Concluding remarks
Chimeric mice with humanized livers have great potential – so far unrealized – to improve modern drug development by alerting researchers to the possibility of adverse hepatic events early in the development process. Recent publications have demonstrated that studies performed using chimeric mice can predict the pattern of human drug metabolism, and in a few limited cases, human drug responses. However, to impact drug development, studies performed in chimeric mice must shift away from the
Acknowledgments
This work is dedicated to the memory of Dr Tatsuji Nomura, whose vision and leadership enabled the TK-NOG project to proceed. G.P. was partially supported by funding from a transformative RO1 award (1R01DK090992) provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). I thank Drs Ying-Ying Guo and Haili Zhang for reviewing this manuscript.
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Genetically Humanized Animal Models
2017, Comprehensive Medicinal Chemistry IIIClinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies with PBPK Modeling
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