Alfuzosin Delays Cardiac Repolarization by a Novel Mechanism

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Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 02/2008; 324(2):427-33. DOI: 10.1124/jpet.107.128405
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The United States Food and Drug Administration (FDA) uses alfuzosin as an example of a drug having QT risk in humans that was not detected in nonclinical studies. FDA approval required a thorough clinical QT study (TCQS) that was weakly positive at high doses. The FDA has used the clinical/nonclinical discordance as a basis for mandatory TCQS, and this requirement has serious consequences for drug development. For this reason, we re-examined whether nonclinical signals of QT risk for alfuzosin were truly absent. Alfuzosin significantly prolonged action potential duration (APD)(60) in rabbit Purkinje fibers (p < 0.05) and QT in isolated rabbit hearts (p < 0.05) at the clinically relevant concentration of 300 nM. In man, the QT interval corrected with Fridericia's formula increased 7.7 ms, which exceeds the 5.0-ms threshold for a positive TCQS. Effects on hK(v)11.1, hK(v)4.3, and hK(v)7.1/hKCNE1 potassium currents and calcium current were not involved. At 300 nM, approximately 30x C(max), alfuzosin significantly increased whole-cell peak sodium (hNa(v)1.5) current (p < 0.05), increased the probability of late hNa(v)1.5 single-channel openings, and significantly shortened the slow time constant for recovery from inactivation. Alfuzosin also increased hNa(v)1.5 burst duration and number of openings per burst between 2- and 3-fold. Alfuzosin is a rare example of a non-antiarrhythmic drug that delays cardiac repolarization not by blocking hK(v)11.1 potassium current, but by increasing sodium current. Nonclinical studies clearly show that alfuzosin increases plateau potential and prolongs APD and QT, consistent with QT prolongation in man. The results challenge the FDA grounds for the absolute primacy of TCQS based on the claim of a false-negative, nonclinical study on alfuzosin.

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Available from: Heather S Eng, Apr 03, 2014
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    • "However, it is widely recognised that extensive focus on hERG has resulted in an overly high attrition rate (false positives) in drug development and that drug pharmacology studies using multiple ion channel effects (MICE) models (Gintant, 2011; Gintant et al., 2006; Kramer et al., 2013) are likely to be more predictive of clinical drug response where compensatory drug actions on one or more other ion channels mitigate or abolish QT prolongation due to hERG blockage (Mirams et al., 2011). Additionally, overly focusing on hERG as the principal suspect for QT prolongation and/or TdP runs the risk of false-negative assignments for drugs such as Alfuzosin that act at ion channels other than hERG (Lacerda et al., 2008). Stem cell derived CMs therefore provide a means to advance the development of MICE assays "
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    ABSTRACT: Human stem cell derived cardiomyocytes (hESC-CM) provide a potential model for development of improved assays for pre-clinical predictive drug safety screening. We have used multi-electrode array (MEA) analysis of hESC-CM to generate multi-parameter data to profile drug impact on cardiomyocyte electrophysiology using a panel of 21 compounds active against key cardiac ion channels. Our study is the first to apply multi-parameter phenotypic profiling and clustering techniques commonly used for high-content imaging and microarray data to the analysis of electrophysiology data obtained by MEA analysis. Our data show good correlations with previous studies in stem cell derived cardiomyocytes and demonstrate improved specificity in compound risk assignment over convention single-parametric approaches. These analyses indicate great potential for multi-parameter MEA data acquired from hESC-CM to enable drug electrophysiological liabilities to be assessed in pre-clinical cardiotoxicity assays, facilitating informed decision making and liability management at the optimum point in drug development. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected] /* */
    Toxicological Sciences 05/2014; 140(2). DOI:10.1093/toxsci/kfu084 · 3.85 Impact Factor
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    • "Indeed, in this study, 28.3% of the hERG inhibitors tested in an APD assay did not prolong repolarization. On the other hand, compounds that prolong QT and APD, but have no effect on the hERG current in vitro include those that prolong repolarization via another mechanism (see Lu et al., 2007; Lacerda et al., 2008 "
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    ABSTRACT: Background and purpose: The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K þ current (I Kr), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a 'first line' test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here. Experimental approach: hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits. Key results: 576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC 50 , 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 mM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts. Conclusion and implications: The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an B15–25% incidence of death. Abbreviations: APD, duration of the action potential; hERG, human ether-a-go-go-related gene; ICH, International Conference on Harmonisation; I Kr , the rapidly activating delayed rectifier potassium current; K þ ATP , ATP-sensitive potassium current; Tp-Te, transmural dispersion; TdP, torsade de pointes; VT, ventricular tachycardia; VF, ventricular fibrillation
    British Journal of Pharmacology 04/2013; 154:1427-1438. · 4.84 Impact Factor
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    ABSTRACT: Characterization of an investigational drug for its QT-liability has become a substantial programme within the drug development paradigm. This evaluation is complicated by the different emphasis placed on various studies by the three different International Conference on Harmonisation (ICH) regions. In view of its significance, assessment of the QT-liability of a drug should, ideally, commence as soon as possible in the drug development process, beginning with nonclinical studies. Depending on its magnitude, and the other ancillary properties of the drug, prolongation of the QT interval can be benign or torsadogenic. The relative rarity of torsade de pointes being triggered by even the highly torsadogenic drugs means that this potentially fatal ventricular tachyarrhythmia is unlikely to be observed in clinical trials, even with drugs that significantly prolong the QT interval. Therefore, the objectives of nonclinical studies should not only be to predict whether a drug will prolong the QT interval in humans but also to distinguish benign from proarrhythmic prolongation of the QT interval.The results from these studies support the planning and interpretation of subsequent clinical studies, particularly in determining the starting and subsequent dose levels and intensity of ECG monitoring in single and multiple ascending dose studies. Furthermore, these nonclinical studies may not only provide the sponsor with an early opportunity to make the all important `go/no-go' decision on the development of a drug, but may also be adequate for the authorities in the EU (but not in North America) to determine whether there is any need for the pivotal E14-compliant thorough QT (TQT) study in healthy volunteers.The conduct of this E14 study requires prior knowledge of the therapeutic dose of the drug and, therefore, cannot usually be undertaken before phase II dose-ranging studies have been completed. Although the ICH E14 guideline focuses on the TQT study, integration of intensive ECG recordings in early phase I and II studies is strongly recommended. This has the dual advantages of generating data that would be required if the TQT study were to be positive and providing data on concentration-QT effect of the drug and its metabolite such that, if the data do allow adequate estimation of the QT prolonging effect of the drug, regulatory authorities may favourably consider a request for a waiver from the E14 study. The E14-compliant study may provide additional data for a more confident `go/no-go' decision. If the TQT study is positive and the decision is to go ahead, ECG data from these early phase I and II studies also allow better planning of intensive ECG monitoring in phase III studies. Understanding the relationship, if any, between the concentration of a drug (and its metabolites) and its QT effect provides important additional information to support regulatory decision making.
    Pharmaceutical Medicine 12/2007; 22(3):151-164. DOI:10.1007/BF03256697
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