Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute

被引:14
|
作者
Vargas, Hugo M. [1 ,12 ]
Rossman, Eric I. [2 ]
Wisialowski, Todd A. [3 ]
Nichols, Jill [4 ]
Pugsley, Michael K. [5 ]
Roche, Brian [6 ]
Gintant, Gary A. [7 ]
Greiter-Wilke, Andrea [8 ]
Kleiman, Robert B. [9 ]
Valentin, Jean-Pierre [10 ]
Leishman, Derek J. [11 ]
机构
[1] Amgen Res, Translat Safety & Bioanalyt Sci, Thousand Oaks, CA 91320 USA
[2] GlaxoSmithKline, Collegeville, PA 19426 USA
[3] Pfizer Worldwide Res, Dev & Med, Safety Pharmacol, Groton, CT USA
[4] Labcorp Early Dev Labs Inc, Madison, WI USA
[5] Cytokinetics, Toxicol, South San Francisco, CA USA
[6] Charles River Labs, Global Safety Pharmacol, Ashland, OH USA
[7] NuPharma Consulting LLC, Boulder, CO USA
[8] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Basel, Switzerland
[9] Clario, Philadelphia, PA USA
[10] UCB Biopharm SPRL, Chemin Foriest, B-1420 Braine Lalleud, Belgium
[11] Eli Lilly & Co, Indianapolis, IN USA
[12] Amgen Inc, Amgen Res Translat Safety & Bioanalyt Sci, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA
关键词
QT prolongation; In vivo cardiovascular telemetry; hERG; Ventricular repolarization; Cardiovascular safety; ICH S7B; ICH E14; S7BQ&As; Integrated risk assessment; SAFETY ASSESSMENT; THOROUGH QT; DE-POINTES; PROLONGATION; INTERVAL; PHARMACOLOGY; SENSITIVITY; MOXIFLOXACIN; REPLACEMENT; TELEMETRY;
D O I
10.1016/j.vascn.2023.107265
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decisionmaking and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e., demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g., supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g., the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).
引用
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页数:10
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