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<p>The safety of drug candidates is routinely evaluated using animal models; however, physiological differences between species can lead to different responses. <i>In vitro</i> safety testing with cells derived from preclinical species can help support mechanistic investigations and assess the relevance, or lack thereof, of <i>in vivo</i> preclinical toxicity findings to human. To that end, liver microtissues (LiMTs) from human&#xa0;(<i>Homo sapiens</i>), rat (<i>Rattus norvegicus</i>), dog (<i>Canis familiaris</i>), and monkey (<i>Macaca fascicularis</i>) were used to investigate the species-specific responses to fialuridine, a nucleoside analogue, that resulted in fatal hepatotoxicity in human clinical trials. The morphology and functionality of these models was assessed over seven days in culture by monitoring ATP levels, albumin production, and cytochrome P450 (CYP450) activity. Fialuridine is markedly more cytotoxic to human LiMTs than to their animal counterparts. Moreover, whole genome transcriptomic analysis showed that fialuridine elicits distinct gene expression responses in human versus animal LiMTs, including the upregulation DNA damage repair pathways and induction of apoptosis. Overall, these findings are consistent with historical clinical and preclinical observations, showing these species-specific LiMTs provide a physiological, scalable, and reproducible <i>in vitro</i> platform for investigating interspecies differences in drug metabolism and hepatotoxicity. Integrating these models into preclinical safety assessment prior to first-in-human studies offers a robust, weight-of-evidence approach to understand species-specific responses and refine human risk assessment.</p>

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Species-specific liver microtissues reveal divergent adverse responses to fialuridine treatment

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

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  • Maria Vittoria Colombo,
  • Agnieszka Pawlowska,
  • Friederike Wenz,
  • Donna Busler,
  • Nicolas Sierro,
  • Yang Xiang,
  • Emmanuel Guedj,
  • Philip Hewitt,
  • Leah M. Norona,
  • Piyush Bajaj,
  • Jonathan P. Jackson,
  • Simon Plummer,
  • Bruno G. H. Filippi

摘要

The safety of drug candidates is routinely evaluated using animal models; however, physiological differences between species can lead to different responses. In vitro safety testing with cells derived from preclinical species can help support mechanistic investigations and assess the relevance, or lack thereof, of in vivo preclinical toxicity findings to human. To that end, liver microtissues (LiMTs) from human (Homo sapiens), rat (Rattus norvegicus), dog (Canis familiaris), and monkey (Macaca fascicularis) were used to investigate the species-specific responses to fialuridine, a nucleoside analogue, that resulted in fatal hepatotoxicity in human clinical trials. The morphology and functionality of these models was assessed over seven days in culture by monitoring ATP levels, albumin production, and cytochrome P450 (CYP450) activity. Fialuridine is markedly more cytotoxic to human LiMTs than to their animal counterparts. Moreover, whole genome transcriptomic analysis showed that fialuridine elicits distinct gene expression responses in human versus animal LiMTs, including the upregulation DNA damage repair pathways and induction of apoptosis. Overall, these findings are consistent with historical clinical and preclinical observations, showing these species-specific LiMTs provide a physiological, scalable, and reproducible in vitro platform for investigating interspecies differences in drug metabolism and hepatotoxicity. Integrating these models into preclinical safety assessment prior to first-in-human studies offers a robust, weight-of-evidence approach to understand species-specific responses and refine human risk assessment.