These findings are consistent with previously reported data overnon-continuous periods in canines (Cools et al.) and NHP's (Chuiet al.) suggesting that a single 24 h assessment period may beinsufficient to determine arrhythmia background for a subject.Although additional investigation is necessary, this data may helpbetter understand the volume of data needed to establish the normalfrequency and type of inherent arrhythmia for a subject. A bestpractice recommendation is to determine the background arrhyth-mia rate in each telemetry subject to aid more accurate interpreta-tion of potential proarrhythmic properties of new test articles.

doi:10.1016/j.vascn.2013.01.123

118

Correlation of cardiovascular parameters with troponin levelsfollowing isoproteronol administration to dogsPeter Harrisa, Jason Cordesa, Jill Steidl-Nicholsa, William Reagana,b,Richard Goldsteina,b, Richard Giovanellia,b,Sandra Summersa,b, Todd Wisialowskia

aGlobal Safety Pharmacology, Pfizer, Groton, CT, USAbBiomarkers, Pfizer, Groton, CT, USA

Evaluation of biomarkers related to cardiac damage is an importantpart of cardiovascular safety assessment of a compound duringdevelopment. This study used the beta agonist isoproterenol to inducehemodynamic and ECG changes that were likely to cause increasedserum cardiac troponin I (cTnI) concentrations to better understand therelationship between routine safety pharmacology endpoints andtroponin as well as other cardiac biomarkers. Telemetry instrumentedBeagle dogs were dosed subcutaneously with isoproterenol 1.0–0.001 mg/kg in decreasing log increments followedby 48 h of telemetrycollection to measure ECG, blood pressure (BP), and left ventricularpressure (LVP with derived+dP/dt). Blood samples were collectedpredose, 4, 7, 24, 48, 72, and 148 h postdose (hpd) for assessment ofcTnI and other related biomarkers. Isoproterenol induced dosedependent increases in cTnI, heart rate, and LVP with a markeddecrease in BP. Heart rate and+dP/dt increased ~100 bpm and6000 mmHg/s respectively, following 1.0 and 0.1 mg/kg isoproterenol.The magnitude and duration of effect were less at lower doses. PeakcTnI levels were 80, 10, and 2 ng/ml and occurred between 4 and 7 hpdwith isoproterenol at doses of 1.0, 0.1, and 0.01, respectively. Increasesin cardiac troponin T, aspartate aminotransferase, and creatine kinasetypically occurredwith a similar timing to the cTnI peak response. Fattyacid binding protein 3 and myosin light chain 3 typically peaked at 4and 24 h, respectively. In conclusion, cTnI is a measurable biomarker ofcardiac damage that correlates well with other standard cardiovascularmeasured endpoints.

doi:10.1016/j.vascn.2013.01.124

119

Comparison of cardiovascular parameter sensitivities intelemeterized rhesus versus cynomolgus monkeysLisa Fitzgerald, Patrick Fanelli, Michael Magee, William Keller,David Reynolds, Min Deng, Tara Grady-Styring, Holly McPherson,Jude Ferraro, Ivy Garfinkel, Alysia Chaves, Chao-Min Hoe,Gregory Friedrichs, Kimberly Hoagland

Merck & Co., Inc., West Point, PA, USA

Safety pharmacology models using conscious unrestrained non-human primates (NHPs) with implanted biotelemetry devices arerecommendedby ICHS7A/S7B guidelines to evaluate the cardiovasculareffects of new chemical entities (NCEs), as they allow for long-termmonitoring of hemodynamic and ECG parameters under low-stresshomeostatic conditions. We characterized baseline cardiovascularprofiles in telemetered rhesus and cynomolgusmonkeys and conductedpower analyses using data from both strains of NHPs. In addition, weevaluated oral doses of dl-sotalol (known hERG channel blocker) inboth strains and compared sensitivities for detecting changes in QT/QTcinterval. Furthermore, a number of correction formulas were assessedfor evaluating QT interval independent of heart rate variation.

Prominent circadian rhythms for blood pressure (BP), heart rate(HR), QT interval and body temperature were evident in both rhesusand cynomolgus monkeys. HRs in rhesus monkeys were 20–50 bpmlower (QT interval values 15 to 30 ms higher) than in cynomolgusmonkeys, with longer PR intervals (15–20%) observed in cynomolgusmonkeys. Dose-related increases in QTc interval after dl-sotaloladministration were observed in both strains of NHPs, confirmingthat both models are valid for preclinical cardiovascular evaluations.Power analyses showed that statistical power to detect changes inQT/QTc interval is slightly higher in rhesus monkeys, which may be aconsequence of HR and behavioral differences between NHP strains.Collectively, we demonstrated that both rhesus and cynomolgusmonkey telemetry models can detect relatively small, but biologi-cally relevant, changes in QT/QTc interval for making decisionsregarding the cardiovascular safety of NCEs.

doi:10.1016/j.vascn.2013.01.125

120

ECG sensitivity evaluation of d,l-sotalol and moxifloxacinin telemetry implanted beagles using an IV solid tip ECGlead configurationAndrea Z. Mitchell, Andrew J. Bills, John J. Kremer,C. Michael Foley, Mark A. Osinski

Covance Laboratories Inc., Madison, WI, USA

Dogs are commonly used to evaluate cardiovascular drug effectsusing radiotelemetry. Mainstream telemetry models include ECG leadplacements subcutaneously on the thorax or on the epicardium in a lead2 configuration. In this study, the negative ECG lead (solid tip) wasplaced in the right jugular vein and the positive lead onto the abdominalside of the diaphragm. Dogs were given two ECG-active reference drugsvia oral gavage and telemetry data were collected continuously for 25 hpostdose. Using a double Latin Square (dLS) design, 8 dogs receiveddose levels of 0, 8, 16, and 32 mg/kg d,l-sotalol. Using a parallel design(PD), 24 dogs (n=6/group) receiveddose levels 0, 10, 30, and100 mg/kgof moxifloxacin: data were analyzed by two approaches: 4 groups(4×4; n=4/group) or 3 groups (3×6; n=6/group; 0, 30, 100 mg/kg).Retrospective power analysis (RPA) was performed for each analysis.Parameters evaluated were PR, QRS, QT, QTc (individual animal based,Fridericia, Bazett, and Van de Water corrections) intervals, heart rate,and blood pressures. Sotalol elicited significant effects on all parametersat all dose levels. Moxifloxacin produced significant effects on QT andQTc at 100 mg/kg using the 4×4 PD and at 30 and 100 mg/kg using the3×6 PD. RPA indicated highest sensitivity for the sotalol dLS design,and higher sensitivity for the 3×6 than the 4×4 moxifloxacin PD. Inconclusion, the IV solid tip lead configuration yields high sensitivity todrug-induced changes in radiotelemetry studies.

doi:10.1016/j.vascn.2013.01.126

Abstractse34