determined if the JET system could detect changes in ECG parametersin NHP implanted previously with a telemetry device (PCT). JET data,especially drug-induced QT prolongation, was compared directlyto PCT-derived data. Three parallel dose groups were used to collectECG for 24 hrs every week (wk) for 4 wks. Group 1 (n=6; JET) wasgiven oral doses of vehicle (veh) weekly; Groups 2 (n=6; JET) and 3(n=6; no JET) were dosed orally as follows: veh (wk1), 8 mg/kg(wk2), 16 mg/kg (wk3) & 32 mg/kg (wk4) SOT. Using a continuousdata analysis approach, JET-derived PR and QRS intervals showed goodtrend agreement with those derived from PCT. In jacketed NHP, SOTproduced dose-related increases in QT and QTc intervals, and reducedHR, as expected. Peak QTc changes of ~50, ~70 and ~120 msec weredetected by the JET system after 8, 16, and 32 mg/kg SOT, respectively.The QTc intervals and changeswere very similar to QTc valuesmeasuredby PCT, and showed minimal discrepancy. In conclusion, the currentfindings clearly support the use of non-invasive JET as a useful tool todetermine cardiac interval changes in toxicology applications in theNHP, with sensitivity to detect drug-induced QTc prolongation.

doi:10.1016/j.vascn.2010.11.083

Poster Number: 80Board Number: 80

Comparison of high definition oscillometry and telemetryfor blood pressure measurements in conscious dogs: Effectsof torcetrapibOlivier Meyer, Roland Jenni, Andrea Greiter-Wilke,Alexander Breidenbach, Henry Holzgrefe

F. Hoffmann-La Roche AG, Basel, Switzerland

Introduction: Absent telemetry, reliable blood pressure (BP)assessments in chronic toxicology studies are currently not feasible.This study compared torcetrapib-induced (T) blood pressure changesin dogs assessed simultaneously by High Definition Oscillometry(HDO) and telemetry.

Methods: Male beagle dogs (n=6) instrumented with ITStelemetry devices received single oral doses of vehicle (soybeanoil), or torcetrapib at 10 and 30 mg/kg. Peripheral and central arterialblood pressures were simultaneously acquired by HDO and telemetry,respectively, for 2 h predose, and for 7 h post dose. Systolic, diastolic,and mean arterial pressures (MAP) and heart rate were compared byAltman-Bland agreement analysis.

Dogs were subdivided into 2 subgroups based upon baseline MAP(GI: <110 and GII: ≥110 mmHg).

Results: Both HDO and telemetry demonstrated high precisionalthough HDO-derived recordings exhibited higher variability for allparameters (the MAP Std. Dev. was 7.0±2.7 vs. 3.4±1.9 mmHg, forHDO and telemetry, respectively), accompanied by a positive bias for allHDO pressures (11.2, 6.4, and 2.7 mmHg for systolic, diastolic, and MAP,respectively). Both methods detected qualitatively and quantitativelysimilar dose-dependent increases in MAP with 30 mg/kg T (15.8±10.4and 15.8±5.3 mmHg for HDO and telemetry, respectively). No sig-nificant effects were noted for heart rate. Telicited a dose-dependent BPincrease in GI whereas in GII the BP increase was maximal with 10 mg/kg and dose-dependence was no longer observed.

Conclusions: These data demonstrate that HDO may provide ausefulmethod for non-invasive BPmeasurements in canine toxicologystudies. Importantly, BP changes were strongly influenced by animaltemperament demonstrating that HDO results must be interpretedwith caution, and within the context of individual subject behavior.

doi:10.1016/j.vascn.2010.11.084

Poster Number: 81Board Number: 81

QTc shortening with a new investigational cancer drugHerbert M. Himmel, Michael Hoffmann

Bayer HealthCare AG, Wuppertal, Germany

Introduction. BAY-79 is an inhibitor of receptor tyrosine kinases withhigh selectivity versus other kinases. Species scaling, complicated bynonlinear pharmacokinetics, predicted a Cmax.u of 36-178 nM at thehuman efficacious exposure. Methods. Preclinical cardiovascular safetypharmacology studies assessed currents (hERG, INa), action potential(AP, rabbit Purkinje fiber), hemodynamic/ECG parameters (anesthetizedBeagle dogs, infusion), and proarrhythmic potential (Screenitô;, Honde-ghem). Results. Both hERG K+ current and hNav1.5 Na+ current wereinhibited with low potency (IC20>10 μM). Purkinje fiber APs remainedunaffected at 10 μM, but at 100 μM displayed reverse use-dependent APduration shortening (APD90 -33% at 1 Hz) and triangulation. Infusion ofBAY-79 into anesthetized dogs was associated with moderate hemody-namic effects (heart rate, stroke volume&macr;, diastolic bloodpressure)and marked QTcV shortening (-25 ms) starting at ~0.65 μM (unbound);QRS was not changed. Assessment of the proarrhythmic potential in theScreenitô; model showed effects (AP duration shortening, instability,coronary flow &macr;, slowed conduction) at ≥30 μM (0.5 hrs/conc.)and at 3 μM with longer exposure (2.5 hrs/conc.). Conclusion. BAY-79 atplasma concentrations slightly higher than those predicted to betherapeutically efficacious in humans is associated with QTc shorteningof unclear mechanistic basis. The QTc shortening associated proarrhyth-mic potential of BAY-79 together with other considerations finallyresulted in an unfavorable risk-benefit assessment.

doi:10.1016/j.vascn.2010.11.085

Poster Number: 82Board Number: 82

An improved placement method of telemetry lead II configurationfor reliable ECG recordings in the conscious ratNicola Fasdelli, Marcello Tontodonati, Roberto Dorigatti,Luciano Cunego, Isabella Callera

GlaxoSmithKline, Verona, Italy

Telemetry represents the gold standard technique for theacquisition of animal haemodynamic and electrocardiographicsignals in the pharmaceutical preclinical development of newchemical entities. In terms of electrocardiographic signal recordingthe quality is well established in large animals, mainly dog, nonhuman primates and minipig, still lacking of satisfactory results inrodents (rat and mouse in particular). In very recent times, anincreasing interest in early safety prediction for the reduction ofcardiovascular attrition has raised in all the major pharmaceuticalcompanies, focusing the interest in particular in the in vivo models.

Two strain of rats commonly used in drug development wereused (i.e., Crl:CD(SD) and Crl:WI rats, from Charles River). Animalsunderwent surgical procedure for the implantation of telemetryprobes (Data Science International, US) for the acquisition of bloodpressure and electrocardiographic signals. A group of rats [N=6/Crl:CD(SD)] was implanted with the standard procedure as described byDSI technical documentation; another group [N=3/Crl:CD(SD)] wasimplanted with the technique as described by Sgoifo et al; a thirdgroup [N=26 Crl:CD(SD), N=Crl:WI male; N=10 Crl:WI female]was implanted with a novel approach designed in our laboratory.

Abstracts e25