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http://dx.doi.org/10.4062/biomolther.2009.17.1.1

Pre-clinical QT Risk Assessment in Pharmaceutical Companies - Issues of Current QT Risk Assessment -  

Takasuna, Kiyoshi (Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.)
Katsuyoshi, Chiba (Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.)
Manabe, Sunao (Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.)
Publication Information
Biomolecules & Therapeutics / v.17, no.1, 2009 , pp. 1-11 More about this Journal
Abstract
Since the Committee for Proprietary Medicinal Products (CPMP) of the European Union issued in 1997 a "points to consider" document for the assessment of the potential for QT interval prolongation by non-cardiovascular agents to predict drug-induced torsades de pointes (TdP), the QT liability has become the critical safety issue in the development of pharmaceuticals. As TdP is usually linked to delayed cardiac repolarization, international guideline (ICH S7B) has advocated the standard repolarization assays such as in vitro IKr (hERG current) and in vivo QT interval, or in vitro APD (as a follow up) as the best biomarkers for predicting the TdP risk. However, the recent increasing evidence suggests that the currently used above biomarkers and/or assays are not fully predictive for TdP, but also does not address potential new druginduced TdP due to the selective disruption of hERG protein trafficking to the cell membrane or VT and/or VF with QT shortening. There is, therefore, an urgent need for other surrogate markers or assays that can predict the proarrhythmic potential of drug candidate. In this review, we provide an ideal pre-clinical strategy to predict the potentials of QT liability and lethal arrhythmia of the drug candidates with recent issues in this field in mind, not at the expense of discarding therapeutically innovative drugs.
Keywords
QT risk; QT liability; hERG; Pre-clinical strategy;
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1 Carlsson, L. (2006). In vitro and in vivo models for testing arrhythmogenesis in drugs. J. Internal. Medicine. 259, 70-80   DOI   ScienceOn
2 Cavero, I., Mestre, M., Guillon, J. M. and Crumb, W. (2003). Drugs that prolong QT interval as an unwanted effect: Assessing their likelihood of inducing hazardous cardiac dysrhythmias. Expert Opin. Pharmacother. 1, 947-973   DOI   ScienceOn
3 Furuhama, K. (2007). Toxicology assessment of fluoroquinolones: A case study. In Nonclinical Drug Safety Assessment: Practical Considerations for Successful Registration(Sietsema, W. K. and Schwen R., Eds.), pp 571-588. FDA news, Falls Church, USA
4 Hashimoto, K. (2008). Torsades de pointes liability inter-model comparisons: The experience of the QT PRODACT initiative. Pharmacol. Ther. 119, 195-198   DOI   ScienceOn
5 Pollard, C. E., Valentin, J. P. and Hammond. T. G. (2008). Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective. Br. J. Pharmacol. 154, 1538-1543   DOI   ScienceOn
6 Sugiyama, A. (2008) Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. Br. J. Pharmacol. 154, 1528-1537   DOI   ScienceOn
7 Tashibu, H., Miyazaki, H., Aoki, K., Akie, Y. and Yamamoto, K. (2005). QT PRODACT: in vivo QT assay in anesthetized dog for detecting the potential for QT interval prolongation by human pharmaceuticals. J. Pharmacol. Sci. 99, 473-486   DOI   ScienceOn
8 Belardinelli, L., Shryock, J. C., Wu, L. and Song, Y. (2005). Use of preclinical assays to predict risk of drug-induced torsades de pointes. Heart Rhythm. 2, S16-S22   DOI   ScienceOn
9 Hanson, L. A., Bass, A. S., Gintant, G., Mittelstadt, S., Rampe, D. and Thomas, K. (2006). ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation. J. Pharmacol. Toxicol. Methods. 54, 116-129   DOI   ScienceOn
10 Camm, A. J. (2005). Clinical trial design to evaluate the effects of drugs on cardiac repolarization: current state of the art. Heart Rhythm. 2, S23-S29   DOI   ScienceOn
11 Liu, T., Brown, B. S., Wu, Y., Antzelevitch, C., Kowey, P. R. and Yan, G. X. (2006). Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias. Heart Rhythm. 3, 948-956   DOI   ScienceOn
12 Lu, H. R., Vlaminckx, E., Hermans, A. N., Rohrbacher, J., Van, Ammel. K., Towart. R., Pugsley, M. and Gallacher, D. J. (2008). Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines. Br. J. Pharmacol. 154, 1427-1438   DOI   ScienceOn
13 Vik, T., Pollard, C. and Sager, P. (2008). Early clinical development: Evaluation of drug-induced torsades de pointes risk. Pharmacol. Ther. 119, 210-214   DOI   ScienceOn
14 Milberg, P., Eckardt, L., Bruns, H. J., Biertz, J., Ramtin, S., Reinsch, N., Fleischer, D., Kirchhof, P., Fabritz, L., Breithardt, G. and Haverkamp, W. (2002). Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: Fast Phase 3 repolarization prevents early after depolarizations and torsade de pointes J. Pharmacol. Exper. Ther. 303, 218-225   DOI   ScienceOn
15 Thomsen M. B., Matz, J., Volders P. G. A. and Vos M. A. (2006). Assessing the proarrhythmic potentials of drugs: Current status of models and surrogate parameters of torsades de pointes arrhythmia. Pharmacol. Ther. 112, 150-170   DOI   ScienceOn
16 Toyoshima, S., Kanno, A., Kitayama, T., Sekiya, K., Nakai, K., Haruna, M., Mino, T., Miyazaki, H., Yano, K. and Yamamoto, K. (2005). QT PRODACT: in vivo QT assay in the conscious dog for assessing the potential for QT interval prolongation by human pharmaceuticals. J. Pharmacol. Sci. 99, 459-471   DOI   ScienceOn
17 Webster, R., Leishman, D. and Walker, D. (2002). Toward a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr. Opin. Drug Discov. Devel. 5, 116-126
18 Hoffmann, P. and Warner, B. (2006). Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends. J. Pharmacol. Toxicol. Methods. 53, 87-105   DOI   ScienceOn
19 Yao, X., Anderson, D. L., Ross, S. A., Lang, D. G., Desai, B. Z., Cooper, D. C., Wheelan, P., McIntyre, M. S., Bergquist, M. L., MacKenzie, K. I., Becherer, J. D. and Hashim, M. A. (2008). Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model. Br. J. Pharmacol. 154, 1446-1456   DOI   ScienceOn
20 Dumotier, B. M. and Georgieva, A. V. (2007). Preclinical cardio-safety assessment of torsadogenic risk and alternative methods to animal experimentation: the inseparable twins. Cell Biol. Toxicol. 23, 293-302   DOI
21 Valentin, J. P., Hoffmann, P., De Clerck, F., Hammond, T. G. and Hondeghem, L. (2004). Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs. J. Pharmacol. Toxicol. Methods. 49, 171-181   DOI   ScienceOn
22 Oros, A., Beekman, J. D. and Vos, M. A. (2008). The canine model with chronic, complete atrio-ventricular block. Pharmacol Ther. 119, 168-178   DOI   ScienceOn
23 Redfern, W. S., Carlsson, L., Davis, A. S., Lynch, W. G., MacKenzie, I., Palethorpe, S., Siegl, P. K., Strang, I., Sullivan, A. T., Wallis, R., Camm, A. J. and Hammond, TG. (2003). Relationship between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58, 32-45   DOI   ScienceOn
24 Carlsson, L. (2008). The anaesthetised methoxamine-sensitised rabbit model of torsades de pointes Pharmacol. Ther. 119, 160-167   DOI   ScienceOn