• Our CiPA Instruments

    HESI FDA BAA study: "Assessing variability and reproducibility of manual and automated patch clamp platforms"

  • CiPA hERG Protocol

    This protocol was used for hERG studies on the Patchliner and SyncroPatch 384PE.

  • HTS CiPA hERG Assay

    Effects of Cisapride using the CiPA hERG protocol on the SyncroPatch 384PE

  • Myocyte & Ion Channel Effects

    Arrhythmic Field potentials in iPSC-derived Cardiomyocytes (CardioExcyte 96) and hERG current inhibition (SyncroPatch 384PE)

  • Gigaseal HTS patch clamp

    CiPA-specified cardiac ion channels recorded at high throughput

  • Gigaseal HTS patch clamp

    High throughput recordings of cardiac ion channels at physiological temperature

  • CardioExcyte 96 screening tool

    CardioExcyte 96 with integrated liquid handling for cardiac safety screening

2020 - Time for a Fully Integrated Nonclinical–Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective

Highlighted Publication in Clinical Pharmacology & Therapeutics (2020)

Authors:
Vargas H.M., Rolf M.G., Wisialowski T.A., Achanzar W., Bahinski A., Bass A., Benson C.T., Chaudhary K.W., Couvreur N., Dota C., Engwall M.J., Foley C.M., Gallacher D., Greiter-Wilke A., Guillon J-M., Guth B., Himmel H.M., Hegele-Hartung C., Ito M., Jenkinson S., Chiba K., Lagrutta A., Levesque P., Martel E., Okai Y., Peri R., Pointon A., Qu Y., Teisman A, Traebert M., Yoshinaga T., Gintant G.A., Leishman D.J., Valentin J-P.

Journal:
Clinical Pharmacology & Therapeutics (2020) doi: 10.1002/cpt.2029


Abstract:

Defining an appropriate and efficient assessment of drug‐induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc‐prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14‐based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B‐based “double‐negative” nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high‐dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double‐negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.


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