Investigation of mechanism of drug-induced cardiac injury and torsades de pointes in cynomolgus monkeys.
OBJECTIVE
Drug candidates must be thoroughly investigated for their potential cardiac side effects. During the course of routine toxicological assessment, the compound RO5657, a CCR5 antagonist, was discovered to have the rare liability of inducing torsades de pointes (polymorphic ventricular arrhythmia) in normal, healthy animals. Studies were conducted to determine the molecular mechanism of this arrhythmia.


METHODS
Toxicological effects of repeat dosing were assessed in naïve monkeys. Cardiovascular effects were determined in conscious telemetry-implanted monkeys (repeat dosing) and anaesthetized instrumented dogs (single doses). Mechanistic studies were performed in guinea-pig isolated hearts and in cells recombinantly expressing human cardiac channels.


RESULTS
In cynomolgus monkeys, RO5657 caused a low incidence of myocardial degeneration and a greater incidence of ECG abnormalities including prolonged QT/QTc intervals, QRS complex widening and supraventricular tachycardia. In telemetry-implanted monkeys, RO5657 induced arrhythmias, including torsades de pointes and in one instance, degeneration to fatal ventricular fibrillation. RO5657 also depressed both heart rate (HR) and blood pressure (BP), with no histological evidence of myocardial degeneration. In the anaesthetized dog and guinea-pig isolated heart studies, RO5657 induced similar cardiovascular effects. RO5657 also inhibited Kv11.1 and sodium channel currents.


CONCLUSIONS
The molecular mechanism of RO5657 is hypothesized to be due to inhibition of cardiac sodium and Kv11.1 potassium channels. These results indicate that RO5657 is arrhythymogenic due to decreased haemodynamic function (HR/BP), decreased conduction and inhibition of multiple cardiac channels, which precede and are probably the causative factors in the observed myocardial degeneration.
Celgene Corporation, San Diego, CA, USA.
D L
DL
Misner
C
C
Frantz
L
L
Guo
M R
MR
Gralinski
P B
PB
Senese
J
J
Ly
M
M
Albassam
K L
KL
Kolaja
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065100:CCR5 Receptor Antagonists; D002219:Carbamates; D004285:Dogs; D015507:Drugs, Investigational / Q000009:adverse effects; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D009930:Organic Chemicals / Q000494:pharmacology*; D010880:Piperidines; D026902:Potassium Channel Blockers / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000009:adverse effects; D015222:Sodium Channels / Q000502:physiology; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D065100:CCR5 Receptor Antagonists; D002219:Carbamates; D015507:Drugs, Investigational; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009930:Organic Chemicals; D010880:Piperidines; D026902:Potassium Channel Blockers; C573863:RO-5657; D026941:Sodium Channel Blockers; D015222:Sodium Channels