QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

Abstract

Abstract. In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n = 3 -4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and / or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation. Supplementary material (Appendix): available only at http://dx

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

“…Nifedipine, which has no QT-prolonging risk in clinic, was reported to cause tachycardia and false QTc interval prolongation in a canine telemetry study using Fridericia's formula (Toyoshima et al, 2005). Verapamil, anoth- Hoppu et al 1991 andSaviuc et al 1993, c Kimura et al 1996, d Zhou et al 1999, e Kirsch et al 2004, f Kawakami et al 2006, g Zhang et al 1999 er calcium channel blocker, also caused tachycardia and false QT-prolonging results in the same canine study (Toyoshima et al, 2005) and in a monkey study using Bazett's formula (Ando et al, 2005). The explanation given for the QTc overestimations was that the heart rate was out of a valid correction range due to hyper-tachycardia (130-170% of baseline value) (Ando et al, 2005;Toyoshima et al, 2005).…”

“…The test drugs and doses administered were astemizole (10 and 30 mg/kg), dl-sotalol (5 and 15 mg/kg), dl-propranolol (30 mg/kg), and nifedipine (30 mg/kg) with at least 1-week interval between administrations of different compounds and different doses. The doses for astemizole and dl-sotalol were determined to exemplify the dose-dependent effects on QT interval, taking into consideration data from a previous study using telemetered cynomolgus monkeys (Ando et al, 2005). The doses of dl-propranolol and nifedipine were selected so that the peak plasma concentration after administration would be over the efficacious concentration in clinic (Rocher et al, 1985;Zylber-Katz et al, 1988).…”

“…However, in vitro tests do not take into account such effects as the potential impact of plasma protein binding, formation of active metabolites, or additional cardiac hemodynamics, and the results may be inconsistent with clinical QT outcomes. The predictability of in vivo tests using telemetered dogs or monkeys for the clinical QT liability of drugs has been validated (Toyoshima et al, 2005;Ando et al, 2005;Hanson et al, 2006) but a considerably larger amount of test substance is needed than with in vitro testing. Recently, common marmosets have been in the limelight as experimental animals in the early development stage because of their small size and thus small amount of test drug needed.…”

“…General correction formulas from Bazett (Bazett, 1920) and Fridericia (Fridericia, 1920) have been used to evaluate the QT liability of drugs in dogs and monkeys (Toyoshima et al, 2005;Ando et al, 2005;Hanson et al, 2006), however, an individual rate correction was recently proposed to be more appropriate (Miyazaki and Tagawa, 2002;Holzgrefe et al, 2007). However, there has been no information available on this individual QT/RR correction method used with common marmosets.…”

Qt-Rr Relationships and Suitable Qt Correction Formulas for Halothane-Anesthetized Dogs

“…However, in conscious animals, spontaneous physiological changes in hemodynamics dependent on posture or activity make the measurement of the QT interval generally more variable than in anesthetized animals. In addition, the Japan Pharmaceutical Manufacturers Association (JPMA) QT PRODACT suggests that a QT study using isoflurane-anesthetized dogs is more accurate to druginduced QT interval prolongation than one using conscious animals (Ando et al, 2005;Tashibu et al, 2005;Toyoshima et al, 2005). Halothane, an anesthetic used for anesthetized studies as well as isoflurane, would help detect the potential risk of drugs to prolong the QT interval with high sensitivity because it inhibits the human ether-a-go-go-related gene (hERG) channel (Li and Correa, 2002), the alpha subunit of rapidly activating delayed rectifier K + currents (I Kr ) mainly responsible for ventricular repolarization, and might potently reduce the repolarization reserve (Biliczki et al, 2002).…”