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Introduction Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes. Methods From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance. Results Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates. Discussion Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10 years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. Methods: Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3–100mg/kg, p.o.) with telemetered ECGs (≥500Hz) obtained for 20–24h post-dose. Individual probabilistic QT–RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc–RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax. Results: All QT–RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. Discussion: The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the implementation of standardized QTc data presentation, QTc reference cycle lengths, and rate-correction coefficients can markedly improve the concordance of preclinical and clinical outcomes in most preclinical species. [Copyright &y& Elsevier]

Abstract: Introduction: Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization safety studies, but it has not been characterized in the cynomolgus monkey. This important experimental animal species exhibits pronounced heart rate variability, complicating the temporal evaluation of QT interval data. Methods: Digitized epicardial ECGs and aortic blood pressures were collected for 20 h in telemetered cynomolgus monkeys (n =6) following the administration of either vehicle or moxifloxacin (10 or 50 mg/kg, p.o.). Moxifloxacin plasma concentrations were determined 4 h postdose. ECG intervals were analyzed by computerized algorithms. Individual probabilistic QT rate-corrections (QTc) were derived from the slopes of predose log-transformed QT–RR data where each QT value was the mean of >250 beats/RR increment. The resulting QTc was used to determine the repolarization effects of moxifloxacin, expressed as the placebo-adjusted change in QTc (ΔQTc), and as the integrated response from 0 to 12 h (AUC0→12) postdose. Results: No ΔQTc effect was produced by 10 mg/kg moxifloxacin. However, moxifloxacin (50 mg/kg; 5.86±0.5 μg/mL C max) significantly prolonged the RR interval by 50 to 112 ms from 3.5 to 7.5 h postdose and ΔQTc by ≥7.2 ms from 1.83 to 9.17 h, with a maximal ΔQTc effect of +26.4 ms. No notable effects on either systemic blood pressure or body temperature occurred with either dose. Discussion: Probabilistic QT rate-corrections appear to have eliminated the confounding effects of heart rate, provided for a stable QTc baseline, and enabled the demonstration of an exposure-dependent QTc prolongation by moxifloxacin. The duration and magnitude of the QTc effect paralleled moxifloxacin pharmacokinetics, and C max values were similar to those achieved clinically in thorough QT/QTc studies. Thus, novel probabilistic QT rate-corrections may offer highly robust assessments of repolarization risk in both nonclinical and clinical investigations. [Copyright &y& Elsevier]

Abstract: Introduction: : QT intervals are not regulated on a beat-to-beat cadence, but are strongly influenced by the preceding heart rate history (hysteresis). ECG sampling, when performed over sufficiently long periods, results in the detection of ranges of different QT values for each discrete RR interval. Given the potential impact of QT hysteresis in QT interval rate-correction procedures, we hypothesized that, physiologically, the QT interval exists as a probabilistic variable where the exact value corresponding to any RR interval is precisely estimated from the associated QT population. Methods:Digital ECGs were collected for 18–21 h in telemetered dogs (n =7) and cynomolgus monkeys (n =7) employing epicardial ECG leads for accurate Tend detection, and analyzed by computerized algorithms. Descriptive statistics were calculated for raw QT values in 10 ms RR increments. Individual rate-corrected QT (QTc) formulae were derived from the slopes of log-transformed QT–RR data where each QT point was the mean of >250 beats/RR increment. The aptness of this QTc model was assessed by residual analysis. Results:Beat-to-beat ECG analysis demonstrated that for all discrete cycle lengths, the associated raw QT intervals were normally distributed populations, spanning approximately 30–40 and 45–100 ms in the dog and cynomolgus monkey, respectively. In both species, QTc was stable (≤5 ms variation) over all physiological RR intervals. Discussion:The probabilistic treatment of raw QT interval populations natively associated to any RR interval provides hysteresis-free raw QT estimates which can be accurately modeled, allowing the derivation of a precise QTc value. Previous unawareness of the probabilistic nature of the QT interval explains the historical failure of numerous QT rate-correction formulae to correctly solve this scientific issue. Importantly, QT distribution analysis has the potential to provide, for the first time, a universal and sensitive method for QT heart rate-correction, providing a robust method for nonclinical and clinical cardiac safety investigations of repolarization delay. [Copyright &y& Elsevier]