Assessing drug safety in human tissues — what are the barriers?

Holmes, Anthony; Bonner, Frank W.; Jones, David R.

doi:10.1038/nrd4662

Cited by 25 publications

(21 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The availability of quality viable human adult heart tissue for cardiac safety studies has been a challenge (Holmes, Bonner, & Jones, 2015). In a focused effort to overcome these limitations, we have set out to first optimize tissue procurement logistics, tissue harvesting and handling methods, and standardized recovery and shipping methods across numerous tissue procurement facilities.…”

Section: Discussionmentioning

confidence: 99%

“…More than half of all development programs are terminated due to safety-related issues, not anticipated by the preclinical studies (Cook et al, 2014). This has called into question the reliability of current preclinical safety-testing paradigms, which rely predominantly on animal models, and has led to demands for more predictive human-relevant tools (Holmes, Bonner, & Jones, 2015). Cardiotoxicity has played a major role in this 'productivity crisis' and remains a predominant cause of drug development discontinuation and withdrawal of marketed drugs (Piccini et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

View full text Add to dashboard Cite

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced proarrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

View full text Add to dashboard Cite

show abstract

“…First, a universal blood substitute is required to support various cell types. [2b,8] Previously developed multiorgan models have used a cell culture medium as a blood substitute. Each organ compartments are connected by microchannels and oxygen, nutrient and various metabolites are transferred through the cell culture medium.…”

Section: Remaining Challenges and Conclusionmentioning

confidence: 99%

“…The development of drugs requires time, effort, and cost for approval, and only an extremely small fraction of drugs (≈10% of the candidates) are approved for clinical applications . The high attrition rate has caused a decrease in the productivity of research and development, making it difficult to create profit from the market and in turn hindering new investments in the development of new drugs . In particular, failures caused by unpredicted problems in the later stages of the drug development process are a serious issue …”

Section: Introductionmentioning

confidence: 99%

Organ‐on‐a‐Chip Technology for Reproducing Multiorgan Physiology

Lee

Sung

2017

Adv Healthcare Materials

View full text Add to dashboard Cite

In the drug development process, the accurate prediction of drug efficacy and toxicity is important in order to reduce the cost, labor, and effort involved. For this purpose, conventional 2D cell culture models are used in the early phase of drug development. However, the differences between the in vitro and the in vivo systems have caused the failure of drugs in the later phase of the drug-development process. Therefore, there is a need for a novel in vitro model system that can provide accurate information for evaluating the drug efficacy and toxicity through a closer recapitulation of the in vivo system. Recently, the idea of using microtechnology for mimicking the microscale tissue environment has become widespread, leading to the development of "organ-on-a-chip." Furthermore, the system is further developed for realizing a multiorgan model for mimicking interactions between multiple organs. These advancements are still ongoing and are aimed at ultimately developing "body-on-a-chip" or "human-on-a-chip" devices for predicting the response of the whole body. This review summarizes recently developed organ-on-a-chip technologies, and their applications for reproducing multiorgan functions.

show abstract

“…29 However, spending continues to increase, with a reported $40 billion expenditure in 2014 in pharmaceutical R&D. 30 Together, this suggests that there is a need for a disruptive technology that allows for a more predictive and efficient drug discovery/development process. 8,31,32 Such technology would have the potential to lead to the discovery of new and improved drugs to treat CVD, while reducing the current patient burden.…”

Section: Challenges and Translational Opportunitiesmentioning

confidence: 99%

Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development

Ribas

Sadeghi

Manbachi

et al. 2016

Applied In Vitro Toxicology

133

View full text Add to dashboard Cite

Cardiovascular diseases are prevalent worldwide and are the most frequent causes of death in the United States. Although spending in drug discovery/development has increased, the amount of drug approvals has seen a progressive decline. Particularly, adverse side effects to the heart and general vasculature have become common causes for preclinical project closures, and preclinical models do not fully recapitulate human dynamics. Recently, organs-on-a-chip technologies have been proposed to mimic the dynamic conditions of the cardiovascular system-in particular, heart and general vasculature. These systems pay particular attention to mimicking structural organization, shear stress, transmural pressure, mechanical stretching, and electrical stimulation. Heart- and vasculature-on-a-chip platforms have been successfully generated to study a variety of physiological phenomena, model diseases, and probe the effects of drugs. Here, we review and discuss recent breakthroughs in the development of cardiovascular organs-on-a-chip platforms, and their current and future applications in the area of drug discovery and development.

show abstract

Assessing drug safety in human tissues — what are the barriers?

Cited by 25 publications

References 3 publications

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Organ‐on‐a‐Chip Technology for Reproducing Multiorgan Physiology

Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development

Contact Info

Product

Resources

About