In vitro secondary pharmacological profiling: An IQ-DruSafe industry survey on current practices

Valentin, Jean‐Pierre; Guillon, Jean‐Michel; Jenkinson, Stephen; Kadambi, Vivek J.; Peri, Ravikumar; Roberts, Sonia; Rosenbrier-Ribeiro, Lyn; Schmidt, Friedemann; Armstrong, Duncan

doi:10.1016/j.vascn.2018.07.001

Cited by 34 publications

(12 citation statements)

References 26 publications

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“…This study demonstrates the utility of the approaches outlined in the recent reports [2], [3], [5]. The diligent evaluation of the nonclinical and clinical data as these are being generated during clinical development can inform the development of strategies to mitigate the risks to the patients and ensure the continuation of the development of safe and effective therapeutics.…”

Section: Discussionmentioning

confidence: 66%

“…The pharmacological approaches used to screen and identify the off-target profile of a drug candidates (secondary pharmacology) are generally consistent across the pharmaceutical industry and typically includes in vitro binding assays for well-known receptors, ion channels, transporters, and enzymes. Positive “hits” for binding activity can be further characterized by determination of potency and functional consequences such as agonism or antagonism [1], [2], [3].…”

Section: Introductionmentioning

confidence: 99%

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Clinical Implications and Translation of an Off-Target Pharmacology Profiling Hit: Adenosine Uptake Inhibition In Vitro

Amouzadeh

Dimery

Werner

et al. 2019

Translational Oncology

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Off-target activities of drug candidates observed during in vitro pharmacological profiling frequently do not translate to adverse events (AEs) in human. This could be because off-target activities do not have functional consequences, are not observed at exposures achieved during clinical testing, or may not translate into clinical outcomes. We report clinical consequences of an off-target activity observed during profiling of AMG 337, a selective inhibitor of the mesenchymal-epithelial transition factor being evaluated for treatment of solid tumors. In our screen of 151 potential off-targets, AMG 337 inhibited only adenosine transporter (AT). During clinical trials, headache emerged as the dose-limiting AE in the first-in-human trial. It was thought that headache was caused by extracellular accumulation of adenosine from inhibition of AT by AMG 337 and subsequent adenosine-mediated vasodilation through adenosine receptors (ARs). Further nonclinical studies were performed to evaluate this hypothesis. AMG 337 inhibited AT function in dog and human cells in vitro and dog and human arteries ex vivo . In a dog telemetry study, AMG 337 caused hypotension, which was reduced by pretreatment with theophylline, an AR antagonist. Overall, nonclinical and clinical data suggested that headache was due to cerebral vasorelaxation caused by AMG 337-mediated inhibition of AT. When subjects were advised to drink coffee, an AR antagonist, prior to AMG 337, the severity of headaches was reduced, allowing them to continue treatment. These findings demonstrate the importance of carefully evaluating clinical observations during early drug development and the value of translational nonclinical studies to investigate the mechanism of action driving clinical observations.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Clinical Implications and Translation of an Off-Target Pharmacology Profiling Hit: Adenosine Uptake Inhibition In Vitro

Amouzadeh

Dimery

Werner

et al. 2019

Translational Oncology

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“…Drug channel/receptor cross-talk cannot be detected in vitro using the hERG assay in transfected HEK/CHO cells because they have a limited number of receptors and second messenger systems that are also expressed in native mammalian cardiac myocytes. This problem highlights the need to perform secondary pharmacology screening assays against multiple receptors, ion channels, transporters, and enzymes to fully understand possible interactions with I Kr ( Bowes et al , 2012 ; Lynch et al , 2017 ; Valentin et al , 2018 ). In general, in vivo QT assays should be used to detect these interactions, with particular attention to differences in receptor expression between species of animals and between animals and humans.…”

Section: Theoretical Reasons For the Lack Of Concordance Observed Bet...mentioning

confidence: 99%

The Challenges of Predicting Drug-Induced QTc Prolongation in Humans

Valentin

Hoffmann²,

Ortemann‐Renon

et al. 2022

Toxicological Sciences

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The content of this manuscript derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between non-clinical repolarization assays and the clinical thorough QT (TQT) study (Vargas et al., 2015). FDA and HESI developed a joint database of non-clinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare performance of three standard non-clinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The non-clinical assays were functional (IKr) current block (hERG), action potential duration (APD), and QTc interval in animals (in vivo QTc). While these non-clinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation (Park et al., 2018). After review, 28 discordant TQT-positive drugs were identified. This manuscript provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and non-clinical assays. We examine six specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/FDA database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate non-clinical data, effects of the drug on other cardiac ion channels, and indirect and/or non-electrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.

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“…Adverse drug reactions (ADRs) usually have an established relationship to undesired interactions of the drug or drug candidate with proteins (off-targets) other than its therapeutic target [38,39,[80][81][82][83]. The pharmaceutical industry generally explores such secondary effects by means of in vitro high throughput screens against a large number of unintended targets (receptors, ion channels, enzymes, transporters) with the aim of limiting off-target interactions and thus reducing liabilities leading to toxicity [84,85].…”

Section: Molecular Targetsmentioning

confidence: 99%

In silico approaches in organ toxicity hazard assessment: Current status and future needs in predicting liver toxicity

Bassan

Alves

Amberg

et al. 2021

Computational Toxicology

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In vitro secondary pharmacological profiling: An IQ-DruSafe industry survey on current practices

Cited by 34 publications

References 26 publications

Clinical Implications and Translation of an Off-Target Pharmacology Profiling Hit: Adenosine Uptake Inhibition In Vitro

Clinical Implications and Translation of an Off-Target Pharmacology Profiling Hit: Adenosine Uptake Inhibition In Vitro

The Challenges of Predicting Drug-Induced QTc Prolongation in Humans

In silico approaches in organ toxicity hazard assessment: Current status and future needs in predicting liver toxicity

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