دورية أكاديمية
Virtual clinical QT exposure-response studies - A translational computational approach.
| العنوان: | Virtual clinical QT exposure-response studies - A translational computational approach. |
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| المؤلفون: | Aguado-Sierra J; Elem Biotech, Barcelona, Spain; Barcelona Supercomputing Center, Barcelona, Spain. Electronic address: jaguado@elem.bio., Dominguez-Gomez P; Elem Biotech, Barcelona, Spain. Electronic address: pdominguez@elem.bio., Amar A; Elem Biotech, Barcelona, Spain. Electronic address: aniamar@elem.bio., Butakoff C; Elem Biotech, Barcelona, Spain. Electronic address: cbutakoff@elem.bio., Leitner M; Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany. Electronic address: michael_2.leitner@boehringer-ingelheim.com., Schaper S; Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany. Electronic address: stefan.schaper.ext@boehringer-ingelheim.com., Kriegl JM; Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany. Electronic address: jan.kriegl@boehringer-ingelheim.com., Darpo B; Clario, Philadelphia, PA, USA. Electronic address: Borje.Darpo@Clario.Com., Vazquez M; Elem Biotech, Barcelona, Spain; Barcelona Supercomputing Center, Barcelona, Spain. Electronic address: mariano@elem.bio., Rast G; Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany. Electronic address: georg.rast@boehringer-ingelheim.com. |
| المصدر: | Journal of pharmacological and toxicological methods [J Pharmacol Toxicol Methods] 2024 Mar-Apr; Vol. 126, pp. 107498. Date of Electronic Publication: 2024 Mar 01. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 9206091 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-488X (Electronic) Linking ISSN: 10568719 NLM ISO Abbreviation: J Pharmacol Toxicol Methods Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Elsevier, c1992- |
| مواضيع طبية MeSH: | Fluoroquinolones*/adverse effects , Long QT Syndrome*/chemically induced , Long QT Syndrome*/drug therapy , Phenethylamines* , Sulfonamides*, Humans ; Dose-Response Relationship, Drug ; Electrocardiography ; Heart Rate ; Moxifloxacin/therapeutic use ; Ondansetron/therapeutic use ; Verapamil |
| مستخلص: | Background and Purpose: A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint. Experimental Approach: Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron. Key Results: Computationally derived concentration-response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms. Conclusion and Implications: Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elem Biotech owns the commercial rights to Alya, the computational finite element solver employed in this study. However, any other commercial or academic finite element solver could be employed to reproduce this work. Elem Biotech owns the commercial rights to Alya, the solver employed in this study. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: 3Rs; Cardiac safety; Computational concentration-QT interval prolongation; Virtual population |
| المشرفين على المادة: | R4Z9X1N2ND (dofetilide) 0 (Fluoroquinolones) U188XYD42P (Moxifloxacin) 4AF302ESOS (Ondansetron) 0 (Phenethylamines) 0 (Sulfonamides) CJ0O37KU29 (Verapamil) |
| تواريخ الأحداث: | Date Created: 20240303 Date Completed: 20240329 Latest Revision: 20240330 |
| رمز التحديث: | 20240331 |
| DOI: | 10.1016/j.vascn.2024.107498 |
| PMID: | 38432528 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1873-488X |
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| DOI: | 10.1016/j.vascn.2024.107498 |