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Cardiovascular Toxicology

, Volume 15, Issue 2, pp 197–202 | Cite as

Analysis of an ECG Record Database Reveals QT Interval Prolongation Potential of Famotidine in a Large Korean Population

  • Jaesuk Yun
  • Eun Hwangbo
  • Jongpill Lee
  • Chong-Run Chon
  • Peol A. Kim
  • In-Hye Jeong
  • Manyoung Park
  • Raewoong Park
  • Shin-Jung Kang
  • Donwoong Choi
Article

Abstract

Some non-antiarrhythmic drugs have the undesirable property of delaying cardiac repolarization, an effect that can be measured empirically as a prolongation of the QT interval by surface electrocardiogram (ECG). The QT prolongation and proarrhythmia potential of famotidine are largely unknown, particularly in individuals that have cardiovascular risk factors such as abnormal electrolyte levels. Based on an analysis of QT/QTc intervals from a database of ECG recordings from a large Korean population (ECG-ViEW, 710,369 ECG recordings from 371,401 individuals), we observed that famotidine administration induced a prolonged QTc interval (above 480 ms, p < 0.05 compared to before-treatment, based on a McNemar test). Furthermore, famotidine induced QT prolongations in 10 out of 14 patients with hypocalcemia and 11 out of 13 patients with hypomagnesemia [difference of mean between before and after famotidine administration; 38.00 ms (95 % confidence interval 2.72–73.28) and 67.08 ms (95 % confidence interval 24.94–109.21), p < 0.05 and p < 0.01 by paired t test, respectively]. In vitro, the IC50 of famotidine for human-ether-a-go-go gene (hERG) channel inhibition was higher than 100 μM as determined by automated patch clamp hERG current assay, implying that hERG channel inhibition is not the underlying mechanism for QT prolongation. These results suggest that famotidine administration increases a proarrhythmic potential, especially in subjects with electrolytes imbalance.

Keywords

QT prolongation Famotidine ECG-ViEW Regulation hERG assay Korean population 

Notes

Acknowledgments

This study was supported by 13171MFDS224 by Ministry of Food and Drug Safety, Republic of Korea.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Shah, R. R. (2005). Drugs, QTc interval prolongation and final ICH E14 guideline : An important milestone with challenges ahead. Drug Safety: An International Journal of Medical Toxicology and Drug Experience, 28, 1009–1028.CrossRefGoogle Scholar
  2. 2.
    Redfern, W. S., Carlsson, L., Davis, A. S., Lynch, W. G., MacKenzie, I., Palethorpe, S., et al. (2003). Relationships 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. Cardiovascular Research, 58, 32–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Darpo, B. (2010). The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance. British Journal of Pharmacology, 159, 49–57.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Stockbridge, N., Morganroth, J., Shah, R. R., & Garnett, C. (2013). Dealing with global safety issues: Was the response to QT-liability of non-cardiac drugs well coordinated? Drug Safety: An International Journal of Medical Toxicology and Drug Experience, 36, 167–182.CrossRefGoogle Scholar
  5. 5.
    Lee, K. W., Kayser, S. R., Hongo, R. H., Tseng, Z. H., & Scheinman, M. M. (2004). Famotidine and long QT syndrome. The American Journal of Cardiology, 93, 1325–1327.CrossRefPubMedGoogle Scholar
  6. 6.
    Sugiyama, A., Satoh, Y., Takahara, A., Nakamura, Y., Shimizu-Sasamata, M., Sato, S., et al. (2003). Famotidine does not induce long QT syndrome: Experimental evidence from in vitro and in vivo test systems. European Journal of Pharmacology, 466, 137–146.CrossRefPubMedGoogle Scholar
  7. 7.
    Endo, T., Katoh, T., Kiuchi, K., Katsuta, Y., Shimizu, S., & Takano, T. (2000). Famotidine and acquired long QT syndrome. The American Journal of Medicine, 108, 438–439.CrossRefPubMedGoogle Scholar
  8. 8.
    Park, M. Y., Yoon, D., Choi, N. K., Lee, J., Lee, K., Lim, H. S., et al. (2012). Construction of an open-access QT database for detecting the proarrhythmia potential of marketed drugs: ECG-ViEW. Clinical Pharmacology and Therapeutics, 92, 393–396.CrossRefPubMedGoogle Scholar
  9. 9.
    Shah, R. R., & Morganroth, J. (2013). ICH E14 Q & A (R1) document: Perspectives on the updated recommendations on thorough QT studies. British Journal of Clinical Pharmacology, 75, 959–965.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Park, M. J., Lee, K. R., Shin, D. S., Chun, H. S., Kim, C. H., Ahn, S. H., et al. (2013). Predicted drug-induced bradycardia related cardio toxicity using a zebrafish in vivo model is highly correlated with results from in vitro tests. Toxicology Letters, 216, 9–15.CrossRefPubMedGoogle Scholar
  11. 11.
    Ayad, R. F., Assar, M. D., Simpson, L., Garner, J. B., & Schussler, J. M. (2010). Causes and management of drug-induced long QT syndrome. Baylor University Medical Center Proceedings, 23, 250–255.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Schechter, E., Freeman, C. C., & Lazzara, R. (1984). Afterdepolarizations as a mechanism for the long QT syndrome: Electrophysiologic studies of a case. Journal of the American College of Cardiology, 3, 1556–1561.CrossRefPubMedGoogle Scholar
  13. 13.
    Gunasekaran, T. S., & DuBrow, I. (1997). Cisapride-induced long QT interval: What is the role of ranitidine? The Journal of Pediatrics, 130, 679–680.CrossRefPubMedGoogle Scholar
  14. 14.
    Nerbonne, J. M., & Kass, R. S. (2005). Molecular physiology of cardiac repolarization. Physiological Reviews, 85, 1205–1253.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jaesuk Yun
    • 1
  • Eun Hwangbo
    • 1
  • Jongpill Lee
    • 1
  • Chong-Run Chon
    • 1
  • Peol A. Kim
    • 1
  • In-Hye Jeong
    • 1
  • Manyoung Park
    • 2
  • Raewoong Park
    • 2
  • Shin-Jung Kang
    • 1
  • Donwoong Choi
    • 1
  1. 1.Pharmaceutical Standardization Research and Testing Division, National Institute of Food and Drug Safety Evaluation (NIFDS)Ministry of Food and Drug Safety (MFDS)Cheongju-siRepublic of Korea
  2. 2.Department of Biomedical InformaticsAjou University School of MedicineSuwonRepublic of Korea

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