Prediction of drug-induced QT interval prolongation in telemetered common marmosets.
Drug-induced QT interval prolongation is a critical issue in development of new chemical entities, so the pharmaceutical industry needs to evaluate risk as early as possible. Common marmosets have been in the limelight in early-stage development due to their small size, which requires only a small amount of test drug. The purpose of this study was to determine the utility of telemetered common marmosets for predicting drug-induced QT interval prolongation. Telemetry transmitters were implanted in common marmosets (male and female), and QT and RR intervals were measured. The QT interval was corrected for the RR interval by applying Bazett's and Fridericia's correction formulas and individual rate correction. Individual correction showed the least slope for the linear regression of corrected QT (QTc) intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. In conclusion, telemetry studies in common marmosets are useful for predicting clinical QT prolonging potential of drugs in early stage development and require only a small amount of test drug.
Tabo
Mitsuyasu
M
Safety Assessment Department, Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka. tabomty@chugai-pharm.co.jp
Hara
Toshiko
T
Sone
Sachiko
S
Shishido
Nobuyuki
N
Kuramoto
Shino
S
Nakano
Kounosuke
K
Onodera
Hideko
H
Kimura
Kazuya
K
Kobayashi
Kazuko
K
D000818:Animals; D016589:Astemizole / Q000494:pharmacology; D002144:Callithrix; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D016589:Astemizole; D011433:Propranolol; D013015:Sotalol; D009543:Nifedipine