Claudia Alvarez Baron

Reassessing the Conduct of Patch Clamp Cardiac Ion Channel Assays to Improve Nonclinical Data Translation to Clinical ECG Changes and Proarrythmia Risk

Claudia Alvarez Baron, Jun Wei Zhao, Donglin Guo, Sabyasachy Mistry et autres

ABSTRACT The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes integrating multi‐cardiac ion channel pharmacology to improve the prediction of drug‐induced Torsade de Pointes (TdP) risk. However, several studies under CiPA have demonstrated misalignment between nonclinical and clinical data. One study showed …

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Integrating drug effects on individual cardiac ionic currents and cardiac action potentials to understand nonclinical translation to clinical ECG changes

Lars Johannesen, Najah Abi‐Gerges, Katrina Sweat, Ana Roup et autres

Concomitant inhibition of the late Na + current (I NaL ) and/or the L-type Ca 2+ current (I CaL ) has been hypothesized to mitigate hERG block-mediated QT C prolongation. This hypothesis was tested in a clinical trial using drugs selected based …

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Assessing variability of hERG data generated using a mock action potential waveform and automated patch clamp platforms – A HESI-coordinated, multi-laboratory comparison of 28 drugs across 3 platforms

Manni Mashaee, Sonja Stoelzle‐Feix, John W. Ridley, Stefano Stabilini et autres

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Variability of manual patch clamp data on Ca 1.2 and Na 1.5 channels generated using standardized protocols and following ICH S7B Q&A 2.1 best practices – Progress update of a HESI-coordinated multi-laboratory study

Huimei Yu, Claudia Alvarez Baron, Jun Zhao, Ming Ren et autres

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Elucidating the challenges with categorizing drugs that block cardiac sodium channels − The impact of temperature on drug-cardiac sodium channel interactions

Huimei Yu, Claudia Alvarez Baron, Jun Wei Zhao, José Vicente et autres

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Multi-laboratory comparisons of manual patch clamp hERG data generated using standardized protocols and following ICH S7B Q&A 2.1 best practices

Claudia Alvarez Baron, Jun Wei Zhao, Huimei Yu, Ming Ren et autres

risk assessment in late-stage clinical development. To interpret the hERG results, understanding hERG assay reproducibility or hERG data variability is pivotal. Protocol and best practice recommendations have been provided with the goal of minimizing lab-to-lab data differences, but the impact remains unclear. …

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hERG block potencies for 5 positive control drugs obtained per ICH E14/S7B Q&As best practices: Impact of recording temperature and drug loss

Claudia Alvarez Baron, Nicolas Thiebaud, Ming Ren, Serge Viatchenko‐Karpinski et autres

According to the ICH S7B guideline, drug candidates are screened for hERG block prior to first-in-human testing to predict the likelihood of delayed repolarization associated with a rare, but life-threatening, ventricular tachyarrhythmia. The new ICH E14 Q&As guideline allows hERG results to …

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Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block

Phu Ngoc Tran, Jiansong Sheng, Aaron L. Randolph, Claudia Alvarez Baron et autres

Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. …

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