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Abstract: Introduction: QT intervals are strongly influenced by preceeding heart rate history and are also characterized by rate-independent variability, leading to difficulty in precise rate-correction of the raw QT interval. The present study elucidates a novel analytical method that effectively addresses this problematic phenomenon in telemetered common marmosets. Methods: ECGs were collected from telemetered common marmosets (male and female) and analyzed by computerized algorithms. Descriptive statistics were calculated from the mean of QT intervals for 5-ms increments of RR. The QT interval was corrected for the RR interval by applying Bazett''s, Fridericia''s, and individual probabilistic QT rate-correction formulae. Results: The linear regression of log-transformed QT and RR intervals derived from a probabilistic approach yielded a well-correlated QT–RR fit. Assessed as the slope of the QTc–RR interval, application of individual probabilistic QT rate-corrections resulted in the most effective dissociation of the effects of rate from the raw QT interval, compared to generic rate-correction formulae. Using individual corrections, the QTc was stable while the interquartile range (IQR) of the QTc distribution was stable, spanning 5–10ms for each subject over all physiological RR intervals. Heart rate variability distributions were centered about unity during both photoperiods and sinus arrhythmia was far less pronounced compared with measurements in dogs. Discussion: Probabilistic QT rate-correction eliminated the confounding effects of heart rate and provided a stable QTc baseline. These results indicate that application of this method of analysis in telemetered common marmosets results in a high degree of sensitivity for the consistent detection of small (5–10ms) changes in the QTc interval. [Copyright &y& Elsevier]

Abstract: Introduction: Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization studies, but it has not been characterized in common marmosets which are uniquely suited to studies in early-stage development due to their small size and minimal test article requirements. The purpose of this study was to evaluate the sensitivity of the common marmoset to detect moxifloxacin-associated QT interval prolongation. Methods: Eight telemetered common marmosets were monitored for 24h following oral administration of moxifloxacin by gavage at 0, 10, 30, and 100mg/kg using a Latin square design. Concurrently, a pharmacokinetic evaluation in 8 non-telemetered animals was conducted. A rate-corrected QT (QTc) interval was derived using an individual probabilistic QT rate-correction. ∆∆QTc (placebo-adjusted QTc change from the individual baseline) was calculated and the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) was analyzed. Results: A slight, but not significant, increase in ∆∆QTc was detected with 10mg/kg of moxifloxacin. Moxifloxacin at 30 and 100mg/kg elicited dose-dependent increases in ∆∆QTc of 14.0±3.6 and 35.0±6.2ms, respectively, with associated total moxifloxacin C max values of 6.5±0.5 and 16.5±1.6µg/mL, respectively. From the PK/PD relationship, the plasma concentration which would attain ∆∆QTc of 5 to 10ms was estimated to be 1.67–3.73µg/mL. The results were consistent with typical clinical trial results (∆∆QTc of 6.6–14.8ms at 2.5–3.5µg/mL). Conclusions: The present study demonstrates that the common marmoset is highly sensitive to moxifloxacin-associated changes in cardiac repolarization, assessed as ∆∆QTc. As such, this species is suitable for precise and reliable detection of small, but significant, drug-associated increases in QTc interval. Thus, the common marmoset should be regarded as a validated animal model for the detection of QT risk in early-stage drug development and represents an important addition to the current in vivo armamentarium. [Copyright &y& Elsevier]