期刊
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
卷 130, 期 -, 页码 5-15出版社
WILEY
DOI: 10.1111/bcpt.13587
关键词
drug development; drug discovery; hepatotoxicity; NASH; organotypic culture; pharmacokinetics
资金
- Innovative Medicines Initiative [875510]
- Vetenskapsradet [2015-02760, 2016-01153, 2016-01154, 2019-01837]
- H2020 European Research Council [742020]
- Cancerfonden [17 0599]
- European Research Council (ERC) [742020] Funding Source: European Research Council (ERC)
- Swedish Research Council [2016-01153, 2016-01154, 2019-01837, 2015-02760] Funding Source: Swedish Research Council
Drug development is a challenging and failure-prone process, with liver toxicity being a major cause of safety failures. The current preclinical systems for compound selection are inadequate, necessitating the development of new strategies to increase clinical success rates. Human liver spheroids are becoming increasingly utilized for various analyses and drug development, showing promise as a new standard in translational pharmacology and toxicology.
Drug development is a failure-prone endeavour, and more than 85% of drugs fail during clinical development, showcasing that current preclinical systems for compound selection are clearly inadequate. Liver toxicity remains a major reason for safety failures. Furthermore, all efforts to develop pharmacological therapies for a variety of chronic liver diseases, such as non-alcoholic steatohepatitis (NASH) and fibrosis, remain unsuccessful. Considering the time and expense of clinical trials, as well as the substantial burden on patients, new strategies are thus of paramount importance to increase clinical success rates. To this end, human liver spheroids are becoming increasingly utilized as they allow to preserve patient-specific phenotypes and functions for multiple weeks in culture. We here review the recent application of such systems for i) predictive and mechanistic analyses of drug hepatotoxicity, ii) the evaluation of hepatic disposition and metabolite formation of low clearance drugs and iii) the development of drugs for metabolic and infectious liver diseases, including NASH, fibrosis, malaria and viral hepatitis. We envision that with increasing dissemination, liver spheroids might become the new gold standard for such applications in translational pharmacology and toxicology.
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