Mechanistic Model‐Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study

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Abstract

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic‐based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell‐derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J‐Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

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Most cited references 30

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Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina.

Bernard Chaitman, Brian Hanley, Adelaide A. Hebert … (2004)

The primary objective of the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial was to determine the dose-response relationship of ranolazine, a potentially new anti-anginal compound, on symptom-limited exercise duration. Fatty acids rise precipitously in response to stress, including acute myocardial ischemia. Ranolazine is believed to partially inhibit fatty acid oxidation, shift metabolism toward carbohydrate oxidation, and increase the efficiency of oxygen use. Patients (n = 191) with angina-limited exercise discontinued anti-anginal medications and were randomized into a double-blind four-period crossover study of sustained-release ranolazine 500, 1,000, or 1,500 mg, or placebo, each administered twice daily for one week. Exercise testing was performed at the end of each treatment during both trough and peak ranolazine plasma concentrations. Exercise duration at trough increased with ranolazine 500, 1,000, and 1,500 mg twice daily by 94, 103, and 116 s, respectively, all greater (p < 0.005) than the 70-s increase on placebo. Dose-related increases in exercise duration at peak and in times to 1 mm ST-segment depression at trough and peak and to angina at trough and peak were also demonstrated (all p < 0.005). Ranolazine had negligible effects on heart rate and blood pressure. One year survival rate combining data from the MARISA trial and its open-label follow-on study was 96.3 +/- 1.7%. In chronic angina patients, ranolazine monotherapy was well tolerated and increased exercise performance throughout its dosing interval at all doses studied without clinically meaningful hemodynamic effects. One-year survival was not lower than expected in this high-risk patient population. This metabolic approach to treating myocardial ischemia may offer a new therapeutic option for chronic angina patients.

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A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes.

Takaaki Uda, Daiju Yamazaki, Atsushi Sugiyama … (2016)

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are anticipated to be a useful tool for conducting proarrhythmia risk assessments of drug candidates. However, a torsadogenic risk prediction paradigm using hiPSC-CMs has not yet been fully established.

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Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

B Darpö, M C Benson, C Dota … (2015)

The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.

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Author and article information

Contributors

David G. Strauss: david.strauss@fda.hhs.gov

Journal

Journal ID (nlm-ta): Clin Pharmacol Ther

Journal ID (iso-abbrev): Clin. Pharmacol. Ther

Journal ID (doi): 10.1002/(ISSN)1532-6535

Journal ID (publisher-id): CPT

Title: Clinical Pharmacology and Therapeutics

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0009-9236

ISSN (Electronic): 1532-6535

Publication date (Electronic): 16 November 2017

Publication date (Print): January 2018

Publication date PMC-release: 16 November 2017

Volume: 103

Issue: 1 , Therapeutic Innovations ( doiID: 10.1002/cpt.v103.1 )

Pages: 54-66

Affiliations

[ ¹ ] Office of New Drugs, Center for Drug Evaluation and Research United States Food and Drug Administration Silver Spring Maryland USA

[ ² ] Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research United States Food and Drug Administration Silver Spring Maryland USA

[ ³ ] Department of Medicine, Division of Cardiology University of Utah Salt Lake City Utah USA

[ ⁴ ] Spaulding Clinical Research West Bend Wisconsin USA

[ ⁵ ] Stanford University Palo Alto California USA

Author notes

[*] [* ]Correspondence: D.G. Strauss ( david.strauss@ 123456fda.hhs.gov )

Article

Publisher ID: CPT896

DOI: 10.1002/cpt.896

PMC ID: 5765372

PubMed ID: 28986934

SO-VID: da4d589b-f263-4fa0-bf6e-13bf0a670ed5

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 25 August 2017

Date revision received : 20 September 2017

Date accepted : 01 October 2017

Page count

Figures: 7, Tables: 1, Pages: 13, Words: 9081

Funding

Funded by: FDA Safety Research Interest Group

Funded by: Critical Path Initiative in the Center for Drug Evaluation and Research

Funded by: FDA's Office of Women's Health

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source-schema-version-number 2.0

component-id cpt896

cover-date January 2018

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:12.01.2018

Mechanistic Model‐Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study

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Abstract

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Most cited references 30

Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina.

A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes.

Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

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