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Drug-Induced Prolongation of the QT Interval: Present and Future Challenges for Drug Discovery

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Pathophysiology and Pharmacotherapy of Cardiovascular Disease

Abstract

Delayed repolarization (manifest as prolongation of the QT interval) is a well-established surrogate marker for a rare but potentially lethal arrhythmia termed torsade de pointes (TdP). Numerous preclinical assays have been developed to detect liabilities associated with drug-induced delayed repolarization across multiple levels of integration (including subcellular, cellular, organ, whole animals) and species (including humans). Off-target effects of noncardiovascular drugs (e.g., terfenadine, cisapride) include block of I Kr (also known as Kv11.1 or hERG), a repolarizing potassium current that plays a prominent role in ventricular repolarization. While contributing to the genesis of TdP, additional drug effects on other cardiac currents that modulate repolarization across different preclinical models must be considered when characterizing drug-induced delayed repolarization and translating proarrhythmic risk to humans. This chapter describes the basis for this important cardiovascular liability facing all small molecule drug candidates, various preclinical proarrhythmia models available to characterize proarrhythmic risk related to delayed repolarization, and evolving future approaches focused on cellular and subcellular mechanism-based in vitro and in silico evaluations of proarrhythmia.

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Abbreviations

ADRs:

Adverse drug reactions

AP:

Action potential

APD:

Action potential duration

AV:

Atrioventricular

CiPA:

Comprehensive in vitro proarrhythmia assay

C max :

Maximum plasma concentration

CVS:

Cardiovascular

EADs:

Early after depolarizations

ECG:

Electrocardiogram

hERG:

Human ether-a-go-go-related gene

IC50 :

Concentration inhibiting 50 % of the response

ICH:

International conference on harmonization

LQTS:

Long QT syndrome

MAPD:

Monophasic action potential duration

NCE:

New chemical entity

PD:

Pharmacodynamic

QTc:

QT interval corrected for heart rate

TdP:

Torsade de pointes

TDR:

Transmural dispersion of repolarization

TQT:

Clinical thorough QT study

TRiAD:

Triangulation, reverse use dependence, instability, and action potential duration

VF:

Ventricular fibrillation

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Authors and Affiliations

  1. Department of Integrative Pharmacology, Integrated Science and Technology, ZR-13, Bldg. AP9, AbbVie, 1 North Waukegan Rd, North Chicago, IL, 60064-6118, USA

    Gary Gintant PhD

  2. Investigative Toxicology, UCB Biopharma SPRL, Chemin du Foriest, B-1420, Braine-l’Alleud, Belgium

    Jean-Pierre Valentin PhD

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Editors and Affiliations

  1. Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, Maryland, USA

    Gowraganahalli Jagadeesh

  2. Pharmacology Unit, AIMST University, Bedong, Malaysia

    Pitchai Balakumar

  3. Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, Maryland, USA

    Khin Maung-U

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Gintant, G., Valentin, JP. (2015). Drug-Induced Prolongation of the QT Interval: Present and Future Challenges for Drug Discovery. In: Jagadeesh, G., Balakumar, P., Maung-U, K. (eds) Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Adis, Cham. https://doi.org/10.1007/978-3-319-15961-4_49

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  • DOI: https://doi.org/10.1007/978-3-319-15961-4_49

  • Publisher Name: Adis, Cham

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