Different Species Require Different Correction Factors For The QT Interval

Soloviev, Maxim; Hamlin, Robert L.; Barrett, Randy M.; Chengelis, Christopher P.; Schaefer, Gerald J.

doi:10.1385/ct:6:2:145

Cited by 29 publications

(5 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The other factor is the difference in basal heart rate, which is considerably higher in dogs. To detect small differences in QT interval, heart rate correction based on population‐based correction factors, such as Bazett and Fridericia, may not be equally applicable to dogs …”

Section: Discussionmentioning

confidence: 99%

Identifying the translational gap in the evaluation of drug‐induced QT_c interval prolongation

Chain

Dubois

Danhof

et al. 2013

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims Given the similarities in QTc response between dogs and humans, dogs are used in pre‐clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l‐sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug‐specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro‐arrhythmic effects of cisapride, d,l‐sotalol and moxifloxacin both in dogs and in humans. The drug‐specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug‐induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro‐arrhythmic potential of a molecule.

show abstract

Section: Discussionmentioning

confidence: 99%

Identifying the translational gap in the evaluation of drug‐induced QT_c interval prolongation

Chain

Dubois

Danhof

et al. 2013

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Segments of ECG data from each telemetry collection during the dosing phase were used to construct a library of representative ECG waveforms for each animal. ECG waveforms that matched the library were analysed to determine ECG parameters, including PR, QT and rate-corrected QT (QTc, using the Bazett's correction; Bazett, 1920;Soloviev et al, 2006) intervals and QRS duration.…”

Section: Data Acquisition and Analysismentioning

confidence: 99%

Detection ofQTcinterval prolongation using jacket telemetry in conscious non‐human primates: comparison with implanted telemetry

Derakhchan

Chui

Stevens

et al. 2013

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEDuring repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter. EXPERIMENTAL APPROACHTwelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg −1 ) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics. KEY RESULTSSotalol attained Cmax values 1-3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg −1 sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT. CONCLUSIONS AND IMPLICATIONSThe current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.

show abstract

“…therefore, use of a parameter calculated by taking heart rate into consideration when calculating the Qt interval, i.e. the corrected Qt interval (Qtc), is recommended [1,2,7,9,13,16,31,32,34,37]. However, there is no such correction formula for cynomolgus monkeys.…”

mentioning

confidence: 99%

Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys

et al. 2020

View full text Add to dashboard Cite

The demand for monkeys for medical research is increasing, because their ionic mechanism of repolarization is similar to that of humans. The QT interval is the distance between the Q wave and T wave, but this interval is affected by heart rate. Therefore, QT correction methods are commonly used in clinical settings. However, an accurate correction formula for the QT interval in cynomolgus monkeys has not been reported. We assessed snapshot electrocardiograms (ECGs) of 353 ketamine-immobilized monkeys, including aged animals, and contrived a new formula for the corrected QT interval (QTc) as a marker of QT interval prolongation in cynomolgus monkeys. Values for QTc were calculated using the formula [QTc] = [QT] / [RR] n , along with several other formulas commonly used to calculate QTc. We found that the optimal exponent of the QT interval corrected for heart rate, n, was 0.576. The mean value of QTc in healthy monkeys determined using the new formula was 373 ± 31 mm, and there were no significant differences between the sexes. Other ECG parameters were not significantly different between the sexes and there were no age-related effects on QTc. Prolongation of QTc to over 405 ms, as calculated by the new formula, was observed in 50 monkeys with underlying diseases. Additionally, all monkeys with QTc above 440 ms by the new formula had some underlying disease. The results resemble those in humans, suggesting that the new QTc formula could be useful for diagnosis of QT interval prolongation in cynomolgus monkeys.

show abstract

Different Species Require Different Correction Factors For The QT Interval

Cited by 29 publications

References 48 publications

Identifying the translational gap in the evaluation of drug‐induced QT_c interval prolongation

Identifying the translational gap in the evaluation of drug‐induced QT_c interval prolongation

Detection ofQTcinterval prolongation using jacket telemetry in conscious non‐human primates: comparison with implanted telemetry

Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys

Contact Info

Product

Resources

About

Different Species Require Different Correction Factors For The QT Interval

Cited by 29 publications

References 48 publications

Identifying the translational gap in the evaluation of drug‐induced QTc interval prolongation

Identifying the translational gap in the evaluation of drug‐induced QTc interval prolongation

Detection ofQTcinterval prolongation using jacket telemetry in conscious non‐human primates: comparison with implanted telemetry

Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys

Contact Info

Product

Resources

About

Identifying the translational gap in the evaluation of drug‐induced QT_c interval prolongation

Identifying the translational gap in the evaluation of drug‐induced QT_c interval prolongation