Preclinical strategies to assess QT liability and torsadogenic potential of new drugs: The role of experimental models

Joshi, Arun B.; DiMino, Tara; Vohra, Yogesh K.; Cui, Changcong; Yan, Gan‐Xin

doi:10.1016/j.jelectrocard.2004.08.003

Cited by 54 publications

(38 citation statements)

References 40 publications

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“…This characteristic of the rabbit ventricle, particularly in female gender, renders it exceptionally sensitive even to weak QT prolonging agents. 2,7,8,27 In the present study, a positive signal for QT prolongation was observed for all drugs with a known TdP risk, even for drugs that tested negative in other preclinical models. For example, terfenadine, a non-cardiac drug with a TdP risk in humans, caused little QT or action potential prolongation in conscious dogs, 28 or in isolated canine Purkinje fibers, 29 porcine myocardium or Purkinje fibers, 30 but prolonged QT interval by more than 20% in the rabbit left ventricular wedge preparation and increased dispersion of repolarization by nearly 50%.…”

Section: Discussionsupporting

confidence: 48%

“…It has also led to a more rigorous review of new drugs by regulatory agencies to determine the potential of such drugs to induce TdP in humans. 2 The development of a preclinical model with high predictive value for the identification of drugs with a TdP liability in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The problem has been validation, that is, providing the predictive value of any preclinical model has been difficult.…”

Section: Introductionmentioning

confidence: 99%

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Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

Liu¹,

Brown²,

Wu³

et al. 2006

Heart Rhythm

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117

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BACKGROUND-The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP.

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Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

Liu¹,

Brown²,

Wu³

et al. 2006

Heart Rhythm

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115

117

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“…Many in vitro and in vivo non-clinical experimental models for detecting the effect of drugs on QT interval or identifying the mechanism behind proarrhythmic effects have been reported (3,4,8,9). An in vitro assay on the K + current through a channel encoded by a human ether-a-go-go-related gene (hERG), that is, a rapid component of the delayed rectifier K + current (I Kr ), as well as in vitro action potential assays using the papillary muscle of guinea pigs or Purkinje fibers from dogs or rabbits and in vivo QT assays using conscious freemoving or anesthetized non-rodent animals have generally been used to evaluate the proarrhythmic potential of new chemical entities in cardiovascular safety pharmacology studies.…”

Section: Introductionmentioning

confidence: 99%

QT PRODACT: Comparison of Non-clinical Studies for Drug-Induced Delay in Ventricular Repolarization and Their Role in Safety Evaluation in Humans

et al. 2005

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Abstract. Drug concentrations that would prolong repolarization parameters by 10%, including action potential duration (APD 90 , APD 30 -90 ), in in vitro assays using guinea-pig papillary muscle and QTc intervals in in vivo assays using conscious dogs, conscious monkeys, and anesthetized dogs were compared. Although, both the in vitro and in vivo assays showed concentrationdependent responses for compounds that have been classified as torsadogenic in humans, only a weak correlation in EC 10 values was observed between the in vitro and in vivo assays. Among the in vivo QT assays, the EC 10 values obtained from conscious dogs, conscious monkeys, and anesthetized dogs correlated well with each other, but the EC 10 values in monkeys were somewhat lower in comparison to those in dogs. When in vivo QT assay EC 10 values were compared to the respective human effective therapeutic plasma concentration (ETPC), the ratios of EC 10 values to ETPCs were less than 20 for most torsadogenic compounds. In conclusion, the relationships between the extent of QTc interval prolongation and the concentration of drugs was highly consistent among the three in vivo models, suggesting that the ratios of EC 10 values in in vivo QT assays are useful for estimating the safety margin of drugs that prolong the QTc interval.

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“…One common electrophysiological finding for those antimalarial drugs associated with QTc prolongation is blockade of the repolarizing potassium channel hERG (human ether-à-go-go-related gene) (24,35,45). To investigate the electrophysiological profile of DHA and PQP, the hERG channel-blocking profile of these compounds, alone and in combination, was characterized in stably expressing human embryonic kidney (HEK-293) cells.…”

mentioning

confidence: 99%

“…For comparison, the hERG channel-blocking effects of chloroquine, dofetilide, halofantrine, lumefantrine, and mefloquine were also evaluated. Previous hERG studies with antimalarials were performed in vitro at room temperature (24,35,45). Under our experimental conditions, the hERG assay was evaluated at 37°C, which provides a more conservative safety evaluation of hERG inhibition (27).…”

mentioning

confidence: 99%

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Borsini

Crumb²,

Pace

et al. 2012

Antimicrob Agents Chemother

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The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (C max ), were expressed as the fold of that particular effect with respect to their C max . The following tests were used at 37°C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (I Na and I Ks , respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemetherlumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and I Na and I Ks analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC 50 ) of halofantrine, which was lower than its C max , was confirmed. All the other compounds blocked hERG, with IC 50 s ranging from 3-to 30-fold their C max s. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its C max were confirmed and DHA blocked it at a concentration about 300-fold its C max . In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the I Na ion current and did so at about 30-fold its C max . No effect on I Ks was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents.

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Preclinical strategies to assess QT liability and torsadogenic potential of new drugs: The role of experimental models

Cited by 54 publications

References 40 publications

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

QT PRODACT: Comparison of Non-clinical Studies for Drug-Induced Delay in Ventricular Repolarization and Their Role in Safety Evaluation in Humans

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

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