Measuring the risk of torsades de pointes: electrocardiographic evaluation of PNU-142093 in conscious cynomolgus non-human primates using restraint and non-restraint procedures.
OBJECTIVE
Drug-induced torsades de pointes (TdP) arrhythmia is a serious public health concern that has significantly slowed the advancement of promising new therapeutic agents to the marketplace. Modeling for the potential to produce TdP has relied in part on the surrogate biomarker QT interval prolongation, measured in vivo in animals and in the clinic in man. This study was a comparison of the effects of PNU-142093, a selective 5HT1D-serotonin receptor agonist, on QT interval prolongation under restraint and non-restraint conditions in conscious cynomolgus non-human primates.


METHODS
Lead II electrocardiograms (ECG) were collected following an oral single-dose (non-restraint conditions using radio-telemetry) and single- and multiple-doses for 14 days (restraint conditions using electrodes applied to the surface) at doses of 0, 5, 15, and 25 mg/kg. ECG were collected from non-restrained animals predose and for up to 5 hrs, and again at 7 hrs, postdose on 4 different days in a Latin-square crossover design; N=4/sex/dose level. ECG were collected from restrained animals on days 1, 7, and 13, predose and at approximately 4 hrs postdose; N=2/sex/group.


RESULTS
Non-restrained animal heart rate ranged from 159+/-22.1 to 168+/-21.4 beats/minute when compared to restrained animal heart rate (ranging from 242+/-17.2 to 246+/-11.5 beats/minute), suggesting that non-restrained animals were under less stress. In non-restrained animals, PNU-142093 produced a non-dose related decrease in heart rate, associated with a dose-related increase in QT and QTc (QT interval corrected for changes in heart rate) intervals, which was accompanied by alterations in T-wave morphology (e.g., widening and notching of the T wave). In restrained non-human primates, PNU-142093 had no effect on heart rate or ECG morphology on any day of dosing and no statistically significant effect on QT or QTc intervals on days 1 or 7 of dosing. By day 13 there were statistically significant increases in QT and QTc intervals at 15 and 25 mg/kg. The increase in QTc interval in restrained animals on day 13 was 29+/-12 and 30+/-19 msec at 15 and 25 mg/kg/day, respectively, and that in non-restrained animals was 65+/-23 and 73+/-28 msec.


CONCLUSIONS
These data demonstrate an ability to detect problematic drugs in conscious cynomolgus non-human primates using both restraint and non-restraint procedures. They further show that the sensitivity of these assays to identify this signal of cardiac risk is significantly improved under the condition of non-restraint.
Bass
Alan S
AS
Drug Safety and Metabolism, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA. alan.bass@spcorp.com
Hanson
Laurie A
LA
Jackson
Terry A
TA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000494:pharmacology; D001578:Benzopyrans / Q000009:adverse effects* / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced; D008252:Macaca fascicularis; D010879:Piperazines / Q000009:adverse effects* / Q000494:pharmacology; D012149:Restraint, Physical; D018570:Risk Assessment; D058825:Serotonin 5-HT1 Receptor Agonists; D013686:Telemetry / Q000379:methods; D016171:Torsades de Pointes / Q000139:chemically induced*
D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; C546227:PNU 142093; D010879:Piperazines; D058825:Serotonin 5-HT1 Receptor Agonists