A new preclinical biomarker for risk of Torsades de Pointes: drug-induced reduction of the cardiac electromechanical window

Evaluation of new therapeutic agents for their potential to cause QT interval prolongation and drug-induced ventricular arrhythmia, like Torsades de Pointes (TdP), is a critical activity during drug development. The QT interval has been used as a surrogate biomarker to assess ventricular repolarization effects caused by drug-induced blockade of cardiac repolarizing currents, mainly I_Kr, but is imperfect in predicting proarrhythmia. Evidence suggests that left ventricular mechanical dysfunction may also contribute to ventricular arrhythmias; thus, electrical and mechanical alterations may have a role in drug-induced TdP. The electromechanical window (EMw) represents the time difference between the end of electrical systole (i.e. the QT interval) and the completion of ventricular relaxation (i.e. the QLVP_end interval), and appears to be a new potential biomarker for TdP risk. A reduction in the EMw (to negative values) has now been shown to be associated with the onset of TdP in an anaesthetized dog model of long QT1 syndrome. Therefore, the EMw represents a novel indicator of TdP risk that may add predictive value beyond assay of drug-induced QT interval prolongation.

LINKED ARTICLE

This article is a commentary on van der Linde et al., pp. 1444–1454 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00934.x     

Dose-response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys

BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.     

QTc interval prolongation by fexofenadine in healthy human volunteers and its correlation with plasma levels of fexofenadine: A demonstration of anticlockwise hysteresis

Aim:

The study was designed to establish relationship between the plasma concentration and QTc interval prolonging effect of fexofenadine and demonstrate the phenomenon of anticlockwise hysteresis.

Materials and Methods:

Six subjects were given fexofenadine 60 mg tablet orally under stable conditions, and their drug concentrations were measured at regular intervals. At predetermined time, their ECGs were recorded. Data were analyzed and plotted graphically.

Design and Setting:

Randomized parallel design, single group study conducted at clinical research organization of Ahmadabad.

Results:

In all subjects time taken for maximum plasma concentration of fexofenadine (T_max) was around 3 h and the value of average maximum plasma concentration was 460.63 ng/mL, the effect of fexofenadine on the heart (measured as QTc interval prolongation) was maximum (E_max) after 6 h and average QTc interval was 469.75 ms. Thus, the time to maximum concentration of fexofenadine did not match with the maximum effect on the heart as measured by QTc interval.

Conclusion:

The relationship between the drug concentration and drug effect on the heart are at two different time scales. It can be understood by two-compartment model of pharmacokinetics, and this retardation or lagging of an effect behind the concentration is known as hysteresis. The increase of QTc was not beyond 500 ms and not sustained, demonstrating overall cardiac safety of fexofenadine.     

The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction

BACKGROUND AND PURPOSE: Body core temperature (Tc) changes affect the QT interval, but correction for this has not been systematically investigated. It may be important to correct QT intervals for drug-induced changes in Tc. EXPERIMENTAL APPROACH: Anaesthetized beagle dogs were artificially cooled (34.2 degrees C) or warmed (42.1 degrees C). The relationship between corrected QT intervals (QTcV; QT interval corrected according to the Van de Water formula) and Tc was analysed. This relationship was also examined in conscious dogs where Tc was increased by exercise. KEY RESULTS: When QTcV intervals were plotted against changes in Tc, linear correlations were observed in all individual dogs. The slopes did not significantly differ between cooling (-14.85+/-2.08) or heating (-13.12+/-3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 degrees C: QTcVcT (QTcV corrected for changes in core temperature)=QTcV-14 (37.5 - Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 degrees C) and marked QTcV shortening (-29%) was induced. After Tc correction, using the above formula, this decrease was abolished. In these re-warmed dogs, we observed significant increases in T-wave amplitude and in serum [K(+)] levels. No arrhythmias or increase in pro-arrhythmic biomarkers were observed. In exercising dogs, the above formula completely compensated QTcV for the temperature increase. CONCLUSIONS AND IMPLICATIONS: This study shows the importance of correcting QTcV intervals for changes in Tc, to avoid misleading interpretations of apparent QTcV interval changes. We recommend that all ICH S7A, conscious animal safety studies should routinely measure core body temperature and correct QTcV appropriately, if body temperature and heart rate changes are observed.