Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

Tamaki, Chihiro; Nagayama, Takashi; Hashiba, Masamichi; Fujiyoshi, Masato; Hizue, Masanori; Kodaira, Hiroshi; Nishida, Motohiro; Suzuki, Kazuhiko; Takashima, Yoshiharu; Ogino, Yamato; Yasugi, Daisaku; Yoneta, Yasuo; Hisada, Shigeru; Ohkura, Takako; Nakamura, Kazuichi

doi:10.2131/jts.38.581

Cited by 65 publications

(44 citation statements)

References 18 publications

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“…Unfortunately, the concordance of clinical chemistry or other biomarkers was not directly compared to establish concordance between preclinical and clinical studies; Several groups advised more use of biomarkers in preclinical and clinical studies [10]. In a subsequent study, adverse drug reactions in each target organ from compounds approved in Japan from 2001–2010 were found to be 48 % concordant between preclinical toxicology studies and humans while changes in laboratory parameters displayed a 30-70 % correlation [11]. It is evident that additional endpoints indicative of organ toxicities that are translatable and/or predictive from preclinical species to human are necessary to improve the safety of compounds in preclinical drug development and clinical trials.…”

Section: Introductionmentioning

confidence: 99%

The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog

et al. 2016

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BackgroundMicroRNAs (miRNA) are ~19–25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein toxicity studies utilizing both species.ResultsA rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of pancreatic injury in the rat and dog.ConclusionsA microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ toxicity in 2 toxicologically relevant species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2956-z) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog

et al. 2016

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“…7 However, such assays using rodent neurons have limitations in predicting the clinical efficacy and neurotoxicity of the candidates due to species differences. 8,9 Thus, using human neurons is a solution to overcome the issue. After the advent of human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), as well as the development of neural differentiation methods, human neurons derived from these stem cells have been applied to the MEA system for the assessment of human neuronal networks.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Human Neuronal Network Assessment System by Using a Human Neuron/Astrocyte Co-Culture Derived from Fetal Neural Stem/Progenitor Cells

et al. 2016

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Using human cell models mimicking the central nervous system (CNS) provides a better understanding of the human CNS, and it is a key strategy to improve success rates in CNS drug development. In the CNS, neurons function as networks in which astrocytes play important roles. Thus, an assessment system of neuronal network functions in a co-culture of human neurons and astrocytes has potential to accelerate CNS drug development. We previously demonstrated that human hippocampus-derived neural stem/progenitor cells (HIP-009 cells) were a novel tool to obtain human neurons and astrocytes in the same culture. In this study, we applied HIP-009 cells to a multielectrode array (MEA) system to detect neuronal signals as neuronal network functions. We observed spontaneous firings of HIP-009 neurons, and validated functional formation of neuronal networks pharmacologically. By using this assay system, we investigated effects of several reference compounds, including agonists and antagonists of glutamate and γ-aminobutyric acid receptors, and sodium, potassium, and calcium channels, on neuronal network functions using firing and burst numbers, and synchrony as readouts. These results indicate that the HIP-009/MEA assay system is applicable to the pharmacological assessment of drug candidates affecting synaptic functions for CNS drug development.

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“…Species differences in DILI are well-recognized [19,20]. The concordance between preclinical animal safety data and human clinical liver toxicity is less than 60%, based on a survey of 150 development compounds.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse

Zhang

He²,

Cai³

et al. 2016

Chemico-Biological Interactions

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Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time– and bile-acid-concentration–dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values <50 μM), but only about 20% of the non-sDILI drugs showed this strength of inhibition in primary human hepatocytes and these drugs are associated only with cholestatic and mixed hepatocellular cholestatic (mixed) injuries. The sDILI drugs, which did not show substantial inhibition of bile salt transport activity, are likely to be associated with immune-mediated liver injury. Twenty-four drugs were also tested in monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune-mediated mechanism, are highly associated with potent inhibition of bile salt transport.

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Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

Cited by 65 publications

References 18 publications

The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog

The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog

Establishment of a Human Neuronal Network Assessment System by Using a Human Neuron/Astrocyte Co-Culture Derived from Fetal Neural Stem/Progenitor Cells

Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse

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