Drug Safety Sciences and the Bottleneck in Drug Development

Watkins, PB

doi:10.1038/clpt.2011.63

Cited by 167 publications

(110 citation statements)

References 12 publications

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“…When liver safety concerns arise for new drug candidates, development may be terminated or larger and longer clinical trials may be required, increasing costs and potentially delaying patient access to new medications 16. Cimaglermin alfa is in development for the treatment of chronic heart failure.…”

Section: Discussionmentioning

confidence: 99%

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Longo

Generaux

Howell

et al. 2017

Clin Pharma and Therapeutics

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Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase I trials were suspended when two cimaglermin alfa‐treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin, meeting current US Food and Drug Administration criteria for a serious liver safety signal (i.e., “Hy's Law”). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death. Using a mathematical model of drug‐induced liver injury (DILIsym) and a simulated population, we estimated that the maximum hepatocyte loss in these two subjects was <13%, which would not result in liver dysfunction sufficient to significantly increase serum bilirubin levels. We conclude that the two subjects should not be considered Hy's Law cases and that mechanistic biomarkers and modeling can aid in refining liver safety risk assessment in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Longo

Generaux

Howell

et al. 2017

Clin Pharma and Therapeutics

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“…3 Presently, hepatotoxicity or cardiac toxicity is the leading cause of withdrawal from the market or termination in drug development in phase I-III. 4 The consequences following DILI, both economic and human are substantial resulting in loss of millions of dollars and hundreds of lives. This review encompasses the epidemiology, causes, risk factors and, causality assessment on DILI and discusses the recent experience from India and the West.…”

mentioning

confidence: 99%

An Update on Drug-induced Liver Injury

Devarbhavi

2012

Journal of Clinical and Experimental Hepatology

141

101

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“…1 In fact, DILI is the leading cause for termination of drug development and withdrawal of approved drugs from the market. 4 It is estimated that 44.3%-87.9% of adult patients in the ICU and 75% of children in the NICU are exposed to a potential DDI. 5 Therefore, more predictive screening methodologies are required to reduce the incidences of DILI and DDIs.…”

Section: Introductionmentioning

confidence: 99%

An Automated Multiplexed Hepatotoxicity and CYP Induction Assay Using HepaRG Cells in 2D and 3D

Ott¹,

Ramachandran²,

Stehno‐Bittel

2017

SLAS Discovery

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Drug-induced liver injury (DILI) and drug-drug interactions (DDIs) are concerns when developing safe and efficacious compounds. We have developed an automated multiplex assay to detect hepatotoxicity (i.e., ATP depletion) and metabolism (i.e., cytochrome P450 1A [CYP1A] and cytochrome P450 3A4 [CYP3A4] enzyme activity) in two-dimensional (2D) and three-dimensional (3D) cell cultures. HepaRG cells were cultured in our proprietary micromold plates and produced spheroids. HepaRG cells, in 2D or 3D, expressed liver-specific proteins throughout the culture period, although 3D cultures consistently exhibited higher albumin secretion and CYP1A/CYP3A4 enzyme activity than 2D cultures. Once the spheroid hepatic quality was assessed, 2D and 3D HepaRGs were challenged to a panel of DILI-and CYP-inducing compounds for 7 days. The 3D HepaRG model had a 70% sensitivity to liver toxins at 7 days, while the 2D model had a 60% sensitivity. In both the 2D and 3D HepaRG models, 83% of compounds were predicted to be CYP inducers after 7 days of compound exposure. Combined, our results demonstrate that an automated multiplexed liver spheroid system is a promising cell-based method to evaluate DILI and DDI for early-stage drug discovery.

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Drug Safety Sciences and the Bottleneck in Drug Development

Cited by 167 publications

References 12 publications

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

An Update on Drug-induced Liver Injury

An Automated Multiplexed Hepatotoxicity and CYP Induction Assay Using HepaRG Cells in 2D and 3D

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