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A comparison of orally-administered (±) verapamil and (±) sotalol on the body temperature, hemodynamics and electrocardiogram of cynomolgus monkeys, beagle dogs, and landrace-duroc pigs
Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 210–258
237
A comparison of orally-administered (±) verapamil and (±) sotalol on the body temperature, hemodynamics and electrocardiogram of cynomolgus monkeys, beagle dogs, and landrace-duroc pigs
This example shows the importance of measuring body temperature in cardiovascular safety studies, and the importance of a correction formula if changes in body temperature are observed.
David V. Gauvin⁎, Jill A. Dalton, Theodore J. Baird Safety Pharmacology and Neurobehavioral Sciences, MPI Research, Mattawan, MI, United States
doi:10.1016/j.vascn.2009.04.117
The impact of body temperature on the QT (QTc) in conscious dogs Introduction: A cross-species validation study was conducted to comply with international cardiovascular safety pharmacology testing guidelines in cynomolgus monkeys, beagle dogs, and standard minipig. Selected doses of verapamil and sotalol were administered and the changes in cardiovascular (hemodynamic and electrocardiographic) endpoints were monitored for 22 continuous hours. Methods: Six monkeys, eight dogs, and four minipigs instrumented with remote radiotelemetry transmitter devices to record the electrocardiogram (ECG; lead II), systolic, diastolic, and mean arterial pressures and body temperature, were singly housed while continuously monitored for 2 h predose and 20 h postdose. Animals were dosed with the test compounds allowing a one week recovery period between doses. Results and discussion: QTc duration was increased dosedependently (an important index of delayed ventricular repolarization) in all three species by sotalol, while ventricular arrhythmias and a variety of other morphological changes in the ECG of freely-moving monkeys, dogs, and pigs were demonstrated following verapamil treatments. Remote radiotelemetry is well equipped to continuously monitor ECG, hemodynamic, and body temperature changes over a protracted postdose interval in all three species towards identifying general trends in calculated interval durations or relatively lowfrequency anomalies (i.e., CV arrhythmias).
doi:10.1016/j.vascn.2009.04.116
Discrepancy between models. Are changes in body temperature sometimes the answer?: A case report H.J. van der Linde⁎, B. Van Deuren, A. Teisman, R. Towart, D.J. Gallacher Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium The cardiovascular safety profile of new medical entities (NMEs) is generally assessed in different pre-clinical in vitro and in vivo models. Often discrepancies or inconsistencies are found between data from these models. Many factors may be responsible for this, but one is often ignored. Namely, it is known that core body temperature (Tc) can influence the QT interval, and recently a formula to correct QTc for changes in Tc has become available (van der Linde et al., Br J Pharmacol, 2008). In this abstract we describe the data from a previously detected NME that affected the Tc and therefore produced misleading in vivo results and discrepancies between different pre-clinical models. An NME inhibited the hERG-mediated membrane K+ current (81.3% at 3 × 10− 6 M) and prolonged QT (+33 ms at 5 × 10− 6 M; p < 0.05) in the isolated Langendorff rabbit heart. In a follow up study in the anaesthetised dog model, this compound dosed up to 40 mg/ kg iv increased heart rate (+69 bpm; p < 0.05), shortened QT (−32 ms; p < 0.05) and induced, in contrast to the previous models, no effect on QTcV (+4 ms; p = 0.20), but significantly increased Tc (+1.2 °C; p < 0.05). After correcting for changes in Tc, using the formula QTcVcT = QTcV − ″14 (37.5 − ″Tc), a prolongation of the QTcVcT (+20 ms; p < 0.05) was noted; thus, confirming the results of the in vitro studies.
Karin Mayer⁎, Anja Klumpp, Thomas Trautmann, Michael Markert, Kurt Schumacher, Brian Guth Boehringer Ingelheim Pharma GmbH & Co., KG Biberach, Germany Introduction: Much effort is made in conducting pre-clinical safety studies to evaluate possible effects of a drug candidate on the ECG, especially the QT-interval. Most of the compounds that were withdrawn from the market were potent inhibitors of the hERG channel and caused QTc prolongation via inhibition of the IKr current. However, there are other mechanisms (e.g. increase in sympathetic tone) that could influence ventricular repolarization time and lead to a prolongation (or shortening) of the QT-interval. One of these is a change in body temperature. We present data demonstrating a direct relationship between the decrease in body temperature and an increase in QTc-interval. Methods: Trained dogs were equipped with ITS radiotelemetry transmitters. Aortic pressure (AP), left ventricular pressure (LVP), ECG lead II and body temperature were continuously monitored over 8 h. After a baseline measurement period of 1 h, dogs received (using a Latin Square cross-over, randomized design) placebo or 5, 15 and 50 mg/kg of a research compound BI xx orally. At 7 h p.a. blood was collected for determination of the plasma exposure. QTc was calculated using the Sarma equation. Results: There was a substantial dose-dependent decrease in body temperature and a simultaneous dose-dependent increase in myocardial repolarization time with 5, 15 and 50 mg/kg BI xx. Discussion: There could be other mechanisms of NCE involved in a change in ventricular repolarization time than direct hERG blockade. We showed an example with an NCE that had no impact on the IKr channel, however, caused significant QTc-prolongation through a substantial decrease in body temperature in conscious dogs.
doi:10.1016/j.vascn.2009.04.118
Effects of body temperature on QT interval in beagle dogs Laurie J. Shellhammer⁎, Maxim Soloviev, Kenneth Kearney, Philip Atterson WIL Research Laboratories, LLC, Ashland, OH, United States Reports on the relationship between core body temperature (CBT) and the duration of QT interval are controversial. Also, investigation of potential drug candidate effects on ventricular repolarization is crucial for pharmaceutical development. To evaluate effects of CBT on ECG, five Beagle dogs (2 males, 3 females) were dosed with drugs that are known to affect CBT but are not known to have QT-liability: 3 mg/kg amphetamine (AM), 30 mg/kg Nembutal (NE), and 30 ug/kg sufentanil (SU); non-treated (NT) animals served as a control. Telemetry data (CBT, blood pressure, and ECG) were collected from implanted animals for a 60-sec period every 10 min (Dataquest A.R.T. Gold 2.3 software, DSI, St. Paul, MN) for 25 h. AM increased CBT up to 2.7 °C for 12 h; NE decreased CBT up to 3.3 °C for 8 h, SU decreased CBT up to 2.3 °C for 24 h. Analysis of all data-points (n = 2267) from treated animals revealed that heart rate (HR) was related to CBT (r = +0.55); uncorrected QT interval showed
237
A comparison of orally-administered (±) verapamil and (±) sotalol on the body temperature, hemodynamics and electrocardiogram of cynomolgus monkeys, beagle dogs, and landrace-duroc pigs
This example shows the importance of measuring body temperature in cardiovascular safety studies, and the importance of a correction formula if changes in body temperature are observed.
David V. Gauvin⁎, Jill A. Dalton, Theodore J. Baird Safety Pharmacology and Neurobehavioral Sciences, MPI Research, Mattawan, MI, United States
doi:10.1016/j.vascn.2009.04.117
The impact of body temperature on the QT (QTc) in conscious dogs Introduction: A cross-species validation study was conducted to comply with international cardiovascular safety pharmacology testing guidelines in cynomolgus monkeys, beagle dogs, and standard minipig. Selected doses of verapamil and sotalol were administered and the changes in cardiovascular (hemodynamic and electrocardiographic) endpoints were monitored for 22 continuous hours. Methods: Six monkeys, eight dogs, and four minipigs instrumented with remote radiotelemetry transmitter devices to record the electrocardiogram (ECG; lead II), systolic, diastolic, and mean arterial pressures and body temperature, were singly housed while continuously monitored for 2 h predose and 20 h postdose. Animals were dosed with the test compounds allowing a one week recovery period between doses. Results and discussion: QTc duration was increased dosedependently (an important index of delayed ventricular repolarization) in all three species by sotalol, while ventricular arrhythmias and a variety of other morphological changes in the ECG of freely-moving monkeys, dogs, and pigs were demonstrated following verapamil treatments. Remote radiotelemetry is well equipped to continuously monitor ECG, hemodynamic, and body temperature changes over a protracted postdose interval in all three species towards identifying general trends in calculated interval durations or relatively lowfrequency anomalies (i.e., CV arrhythmias).
doi:10.1016/j.vascn.2009.04.116
Discrepancy between models. Are changes in body temperature sometimes the answer?: A case report H.J. van der Linde⁎, B. Van Deuren, A. Teisman, R. Towart, D.J. Gallacher Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium The cardiovascular safety profile of new medical entities (NMEs) is generally assessed in different pre-clinical in vitro and in vivo models. Often discrepancies or inconsistencies are found between data from these models. Many factors may be responsible for this, but one is often ignored. Namely, it is known that core body temperature (Tc) can influence the QT interval, and recently a formula to correct QTc for changes in Tc has become available (van der Linde et al., Br J Pharmacol, 2008). In this abstract we describe the data from a previously detected NME that affected the Tc and therefore produced misleading in vivo results and discrepancies between different pre-clinical models. An NME inhibited the hERG-mediated membrane K+ current (81.3% at 3 × 10− 6 M) and prolonged QT (+33 ms at 5 × 10− 6 M; p < 0.05) in the isolated Langendorff rabbit heart. In a follow up study in the anaesthetised dog model, this compound dosed up to 40 mg/ kg iv increased heart rate (+69 bpm; p < 0.05), shortened QT (−32 ms; p < 0.05) and induced, in contrast to the previous models, no effect on QTcV (+4 ms; p = 0.20), but significantly increased Tc (+1.2 °C; p < 0.05). After correcting for changes in Tc, using the formula QTcVcT = QTcV − ″14 (37.5 − ″Tc), a prolongation of the QTcVcT (+20 ms; p < 0.05) was noted; thus, confirming the results of the in vitro studies.
Karin Mayer⁎, Anja Klumpp, Thomas Trautmann, Michael Markert, Kurt Schumacher, Brian Guth Boehringer Ingelheim Pharma GmbH & Co., KG Biberach, Germany Introduction: Much effort is made in conducting pre-clinical safety studies to evaluate possible effects of a drug candidate on the ECG, especially the QT-interval. Most of the compounds that were withdrawn from the market were potent inhibitors of the hERG channel and caused QTc prolongation via inhibition of the IKr current. However, there are other mechanisms (e.g. increase in sympathetic tone) that could influence ventricular repolarization time and lead to a prolongation (or shortening) of the QT-interval. One of these is a change in body temperature. We present data demonstrating a direct relationship between the decrease in body temperature and an increase in QTc-interval. Methods: Trained dogs were equipped with ITS radiotelemetry transmitters. Aortic pressure (AP), left ventricular pressure (LVP), ECG lead II and body temperature were continuously monitored over 8 h. After a baseline measurement period of 1 h, dogs received (using a Latin Square cross-over, randomized design) placebo or 5, 15 and 50 mg/kg of a research compound BI xx orally. At 7 h p.a. blood was collected for determination of the plasma exposure. QTc was calculated using the Sarma equation. Results: There was a substantial dose-dependent decrease in body temperature and a simultaneous dose-dependent increase in myocardial repolarization time with 5, 15 and 50 mg/kg BI xx. Discussion: There could be other mechanisms of NCE involved in a change in ventricular repolarization time than direct hERG blockade. We showed an example with an NCE that had no impact on the IKr channel, however, caused significant QTc-prolongation through a substantial decrease in body temperature in conscious dogs.
doi:10.1016/j.vascn.2009.04.118
Effects of body temperature on QT interval in beagle dogs Laurie J. Shellhammer⁎, Maxim Soloviev, Kenneth Kearney, Philip Atterson WIL Research Laboratories, LLC, Ashland, OH, United States Reports on the relationship between core body temperature (CBT) and the duration of QT interval are controversial. Also, investigation of potential drug candidate effects on ventricular repolarization is crucial for pharmaceutical development. To evaluate effects of CBT on ECG, five Beagle dogs (2 males, 3 females) were dosed with drugs that are known to affect CBT but are not known to have QT-liability: 3 mg/kg amphetamine (AM), 30 mg/kg Nembutal (NE), and 30 ug/kg sufentanil (SU); non-treated (NT) animals served as a control. Telemetry data (CBT, blood pressure, and ECG) were collected from implanted animals for a 60-sec period every 10 min (Dataquest A.R.T. Gold 2.3 software, DSI, St. Paul, MN) for 25 h. AM increased CBT up to 2.7 °C for 12 h; NE decreased CBT up to 3.3 °C for 8 h, SU decreased CBT up to 2.3 °C for 24 h. Analysis of all data-points (n = 2267) from treated animals revealed that heart rate (HR) was related to CBT (r = +0.55); uncorrected QT interval showed