Cardiac repolarization

The QT interval is a dynamic physiological variable depending on multiple factors such as cardiac cycle length (heart rate), autonomic nervous system activity, age, gender, plasma electrolyte concentrations, genetic variations in ion channels involved in cardiac repolarization. In addition, circadian and seasonal variations of the QT interval have been described [93]. 

Different laboratories may yield different IC50 values Activity of metabolites and enantiomers must be studied Compounds insoluble in water are difficult to assess Species vary in type and distribution of ion channel involved in cardiac repolarization... 

ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. Specifically, it calls for a clinical thorough QT/QTc study (typically conducted in healthy volunteers), which is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarization, as detected by QT/QTc interval prolongation. 

Subject variability High intraindividual variability in QTc values (circadian and seasonal variation law of regression to the mean) High interindividual variability in QTc values (males versus females) Unknown prevalence in the general population of subjects carrying silent mutations in the ion channels responsible for cardiac repolarization (these subjects have normal QTc value but reduced repolarization reserve) Variability in the individual metabolic capacity for a given drug... 

Another unanswered question is the evaluation of the effect on cardiac repolarization of oncologic drugs, for which the thorough QT/QTc study in volunteers cannot be performed [166], In these cases, not only central tendency (i.e. mean QTc increase) and proportion of outliers but also other findings such as syncope, ventricular tachyarrhythmias and other cardiac effects should be more closely defined. 

Morganroth, J. (2007) Cardiac repolarization and the safety of new drugs defined by electrocardiography. Clinical Pharmacology and Therapeutics, 81, 108-113. 

Morganroth, J. (2007) Evaluation of the effect on cardiac repolarization (QTc interval) of oncologic drugs. Ernst Schering Research Foundation Workshop, Springer-Verlag, Berlin, 171-184. 

Rudy, Y. (2006) Modelling and imaging cardiac repolarization abnormalities. Journal of Internal Medicine, 259, 91-106. 

Provides the general framework for in vitro and in vivo Anon.25 safety pharmacology studies, including studies addressing the risk for a drug to slow cardiac repolarization... 

Anderson, M.E., Al-Khatib, S.M., Roden, D.M., and Califf, R.M., Cardiac repolarization current knowledge, criticl gaps and new approaches to drug development and patient management, Am. Heart., 144, 769-781, 2002. 

Martin, R.L., McDermott, J.S., Salmen, H.J., Palmatier, J., Cox, B.F., and Gintant, G.A., The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization influence of multi-channel block, /. Cardiovasc. Pharmacol, 43, 369-379, 2004. 

Proarrhythmia Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization, is the most common form of proarrhythmia associated with sotalol, occurring in approximately 4% of high-risk patients. 

Honig PK, Wortham DC, Lazarev A, Cantilena LR. Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine. J Clin Pharmacol 1996 36(4) 345-351. 

Ibutilide slows cardiac repolarization by blockade of the rapid component (I ) of the delayed rectifier potassium current. Activation of... 

Ibutilide slows cardiac repolarization by blockade of the rapid component of the delayed rectifier potassium current. Activation of slow inward sodium current has also been suggested as an additional mechanism of action. After intravenous administration, ibutilide is rapidly cleared from the plasma by hepatic metabolism. The metabolites are excreted by the kidney. The elimination half-life averages 6 hours. 

Tegaserod has no known effects on cytochrome P450 enzymes and no known drug interactions. Unlike cisapride, tegaserod does not inhibit cardiac repolarization and does not prolong the QT interval. 

Perfusion of newborn rabbit myocytes with anti-Ro/La results in reduction of cardiac repolarization and alteration of calcium transport (A13, A14). 

A13. Alexander, E. L., Buyon, I. P., Lane, J., Lafond-Walker, A., Provost, T. T., and Guamieri, T., Anti-SS-A/Ro SS-B /La antibodies bind to neonatal rabbit cardiac cells and preferentially inhibit in vitro cardiac repolarization. J. Autoimmun. 2,463-469 (1989). 

Bezzina CR, Verkerk AO, Busjahn A, Jeron A, Erdmann J, Koopmann TT, Bhuiyan ZA, Wilders R, Mannens MM, Tan HL, Luft FC, Schunkert H, Wilde AA. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res 2003 59 27-36. 

The occurrence of cardiac toxicity was closely correlated with terfenadine use, and subsequent in vitro studies confirmed that terfenadine (but not fexofenadine) efficiently blocks cardiac potassium channels (14). A study in healthy volunteers treated concomitantly with terfenadine and ketoconazole found a linear relationship between trough terfenadine concentrations and QTC intervals. The QTC interval lengthened up to 110 millisecond at the highest plasma concentrations of 45 ng/mL (9). Thus, the direct inhibitory effect of terfenadine on cardiac potassium channels results in prolongation of cardiac repolarization, which is a well-known cause of ventricular arrhythmias. In one death in which terfenadine was implicated, plasma level of the drug was 55 ng/mL several hours after the last ingestion of the drug (when it normally should be undetectable). 

Bezzina, C.R. et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res 2003, 59 27-36. 

Kahfa M, Drolet B, Daleau P et al. (1999) Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine Hi antagonist diphenhydramine. J Pharmacol Exp Ther 288 858-865... 

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