Early Investigation of QTc Liability

The Role of Multiple Ascending Dose (MAD) Study

Abstract

The International Conference on Harmonization (ICH) guidance note E14 requires a thorough QT (TQT) study to characterize proactively the potential of a new drug to affect cardiac repolarization, as determined by prolongation of the corrected QT (QTc) interval. A typical TQT study is reviewed herein with a discussion on various practical issues concerning the use of a supratherapeutic dose, establishing assay sensitivity, the application of QT rate-correction methods, and restricting analyses of ECGs and plasma samples to key timepoints.

We then discuss, and provide examples of, how multiple ascending dose (MAD) study protocols can be modified to integrate robust ECG monitoring and analyses to gather key information provided by a TQT study. Among the main advantages of this approach are the ability to study the ECG effects of a wide range of doses to the maximum tolerated doses, eliminating routine analyses at unnecessary timepoints, making early go-no-go decisions, making phase II studies more efficient and, if necessary, being able to implement rigorous ECG monitoring in populations and pivotal studies of regulatory interest. If clear evidence for the presence or absence of QTc effect is found, the data from a modified MAD study may support a request for a waiver from the requirement to conduct a TQT study. In the event that a TQT study is considered unnecessary, there are obvious significant savings without compromising collection of vital safety data.

This is a preview of subscription content, access via your institution.

Table I
Table II
Table III

References

  1. 1.

    Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol 2002; 54: 188–202

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Shah RR. If a drug deemed ‘safe’ in nonclinical tests subsequently prolongs QT in phase 1 studies, how can its sponsor convince regulators to allow development to proceed? Pharmacol Ther 2008; 119: 215–21

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Committee for Proprietary Medicinal Products. Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products (CPMP/986/96). London: EMEA, 1997 Dec 17 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/briefing/pubs/cpmp.pdf [Accessed 2012 Jan 26]

  4. 4.

    Committee for Medicinal Products for Human Use. ICH note for guidance on the nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (ICH S7B) [CHMP/ICH/423/02]. London: EMEA, 2005 Nov [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002841.pdf [Accessed 2012 Jan 26]

  5. 5.

    Committee for Medicinal Products for Human Use. ICH note for guidance on the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (ICH E14) [CHMP/ICH/2/04]. London: EMEA, 2005 Nov [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002879.pdf [Accessed 2012 Jan 26]

  6. 6.

    Committee for Medicinal Products for Human Use. ICH Topic E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Questions and Answers (EMEA/CHMP/ICH/310133/2008). EMEA, London, June 2008 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002878.pdf [Accessed on 2012 Jan 26]

  7. 7.

    Shah RR. Drugs, QT interval prolongation and ICH E14: the need to get it right. Drug Saf 2005; 28: 115–25

    Article  PubMed  Google Scholar 

  8. 8.

    Beasley Jr CM, Dmitrienko A, Mitchell MI. Design and analysis considerations for thorough QT studies employing conventional (10 s, 12-lead) ECG recordings. Expert Rev Clin Pharmacol 2008; 1: 815–39

    Article  PubMed  Google Scholar 

  9. 9.

    Darpo B. The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance. Br J Pharmacol 2010; 159:49–57

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Malik M, Garnett CE, Zhang J. Thorough QT Studies: questions and quandaries. Drug Saf 2010; 33: 1–14

    Article  PubMed  Google Scholar 

  11. 11.

    Salvi V, Karnad DR, Panicker GK, et al. Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development. Br J Pharmacol 2010; 159: 34–48

    Article  PubMed  Google Scholar 

  12. 12.

    Morganroth J. Cardiac repolarization and the safety of new drugs defined by electrocardiography. Clin Pharmacol Ther 2007; 81: 108–13

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Shah RR. Drug-induced prolongation of the QT interval: regulatory dilemmas and implications for approval and labelling of a new chemical entity. Fundam Clin Pharmacol 2002; 16: 147–56

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Hutmacher MM, Chapel S, Agin MA, et al. Performance characteristics for some typical QT study designs under the ICH E14 guidance. J Clin Pharmacol 2008; 48: 215–24

    Article  PubMed  Google Scholar 

  15. 15.

    Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 2008; 48: 13–8

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Malik M, Färbom P, Batchvarov V, et al. Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart 2002; 87: 220–8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Batchvarov VN, Ghuran A, Smetana P, et al. QT-RR relationship in healthy subjects exhibits substantial inter-subject variability and high intrasubject stability. Am J Physiol Heart Circ Physiol 2002; 282: H2356–63

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Malik M, Hnatkova K, Batchvarov V. Differences between study-specific and subject-specific heart rate corrections of the QT interval in investigations of drug induced QTc prolongation. Pacing Clin Electrophysiol 2004; 27: 791–800

    Article  PubMed  Google Scholar 

  19. 19.

    Malik M. The imprecision in heart rate correction may lead to artificial observations of drug induced QT interval changes. Pacing Clin Electrophysiol 2002; 25: 209–16

    Article  PubMed  Google Scholar 

  20. 20.

    Beasley Jr CM, Mitchell MI, Dmitrienko AA, et al. The combined use of ibutilide as an active control with intensive electrocardiographic sampling and signal averaging as a sensitive method to assess the effects of tadalafil on the human QT interval. J Am Coll Cardiol 2005; 46: 678–87

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Vandemeulebroecke M, Lembcke J, Wiesinger H, et al. Assessment of QTc-prolonging potential of BX471 in healthy volunteers: a ‘thorough QTc study’ following ICH E14 using various QT correction methods. Br J Clin Pharmacol 2009; 68: 435–46

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Extramiana F, Maison-Blanche P, Badilini F, et al. Individual QT-R-R relationship: average stability over time does not rule out an individual residual variability: im plication for the assessment of drug effect on the QT in terval. Ann Noninvasive Electrocardiol 2005; 10: 169–78

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Yan LK, Zhang J, Ng MJ, et al. Statistical characteristics of moxifloxacin-induced QTc effect. J Biopharm Stat 2010; 20: 497–507

    Article  PubMed  Google Scholar 

  24. 24.

    Zhang J. Testing for positive control activity in a thorough QTc study. J Biopharm Stat 2008; 18: 517–28

    Article  PubMed  Google Scholar 

  25. 25.

    Kimura M, Umemura K, Ikeda Y, et al. Pharmacokinetics and pharmacodynamics of (+/−)-sotalol in healthy male volunteers. Br J Clin Pharmacol 1996; 42: 583–8

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    van Haarst AD, van ‘t Klooster GA, van Gerven JM, et al. The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 1998; 64: 542–6

    Article  PubMed  Google Scholar 

  27. 27.

    Abernethy DR, Wesche DL, Barbey JT, et al. Stereo-selective halofantrine disposition and effect: concentration-related QTc prolongation. Br J Clin Pharmacol 2001; 51: 231–7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Somberg JC, Preston RA, Ranade V, et al. QT prolongation and serum sotalol concentration are highly correlated following intravenous and oral sotalol. Cardiology 2010; 116: 219–25

    Article  PubMed  Google Scholar 

  29. 29.

    Morganroth J. Response to “Design of the ‘thorough QT study’”. Clin Pharmacol Ther 2008; 83: 529–30

    Article  Google Scholar 

  30. 30.

    Zhang J, Stockbridge N. Selection of the time points for a thorough QTc study. Drug Inform J 2011; 45: 713–5

    Article  Google Scholar 

  31. 31.

    Darpo B, Sager P. Design of the “thorough QT study”. Clin Pharmacol Ther 2008; 83: 528–9

    Article  Google Scholar 

  32. 32.

    Kligfield P, Green CL, Mortara J, et al. The Cardiac Safety Research Consortium electrocardiogram warehouse: thorough QT database specifications and principles of use for algorithm development and testing. Am Heart J 2010; 160: 1023–8

    Article  PubMed  Google Scholar 

  33. 33.

    Tyl B, Kabbaj M, Fassi B, et al. Comparison of semi-automated and fully automated methods for QT measurement during a horough QT/QTc study: variability and sample size considerations. J Clin Pharmacol 2009; 49:905–15

    Article  PubMed  Google Scholar 

  34. 34.

    Rawlins MD. Cutting the cost of drug development? Nat Rev Drug Discov 2004; 3: 360–4

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Bouvy JC, Koopmanschap MA, Shah RR, et al. The cost-effectiveness of drug regulation: the example of thorough QT/QTc studies. Clin Pharmacol Ther 2012; 91: 281–8

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    ClinicalTrials.gov, a service of the US National Institutes of Health [online]. Available from URL: http://clinialtrials.gov [Accessed 2012 Mar 10]

  37. 37.

    Morganroth J, Talbot GH, Dorr MB, et al. Effect of single ascending, supratherapeutic doses of sparfloxacin on cardiac repolarization (QTc interval). Clin Ther 1999; 21: 818–28

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Morganroth J, Hunt T, Dorr MB, et al. The cardiac pharmacodynamics of therapeutic doses of sparfloxacin. Clin Ther 1999; 21: 1171–81

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Food and Drug Administration, Center for Drug Evaluation and Research. Celexa (citalopram hydrobromide): review of applications no: 020822Orig1s038, s040 and 021046Orig1s016, s017. Silver Spring (MD): FDA, 2011 Aug 12 [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/020822Orig1s038s040_021046Orig1s016s017Rev.pdf [Accessed 2012 Jan 26]

  40. 40.

    Garnett CE, Zhu H, Malik M, et al. Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am Heart J 2012; 163: 912–30

    Article  PubMed  Google Scholar 

  41. 41.

    Florian JA, Tornøe CW, Brundage R, et al. Population pharmacokinetic and concentration-QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies. J Clin Pharmacol 2011; 51: 1152–62

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Zhang J. Novel approaches to TQT study design and analysis. A presentation at the 3rd DIA Cardiac Safety Work shop; 2012 May 28-29; Tokyo

  43. 43.

    Shah RR. Drug-induced QT interval prolongation regulatory guidance and perspectives on hERG channel studies. In: Chadwick J, Goode J, editors. The hERG potassium channel: structure, function and long QT syndrome. (Novartis Foundation Symposium No. 266.) Chichester: Wiley Publications, 2005: 251–85

    Google Scholar 

  44. 44.

    Ulens C, Daenens P, Tytgat J. Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc Res 1999; 44: 568–78

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Shah RR, Morganroth J. Evaluating the QT-liability of a drug during its development. Pharm Med 2008; 22: 151–64

    Article  Google Scholar 

  46. 46.

    Rohatagi S, Carrothers TJ, Kuwabara-Waqq J, et al. Is a thorough QTc study necessary? The role of modeling and simulation in evaluating the QTc prolongation potential of drugs. J Clin Pharmacol 2009; 49: 1284–96

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Food and Drug Administration. Darvon (propoxyphene): Multiple Ascending Dose (MAD) study review submission number: SDN 039/040, 3 September 2010. Silver Spring (MD): FDA, 2011 Aug 12 [online]. Available from URL: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234330.pdf [Accessed 2012 Mar 4]

Download references

Acknowledgements

The authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). The authors have not received any financial support for writing this article. Rashmi Shah was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and the ICH E14 Topic Leader, representing the EU. Joel Morganroth is the Chief Cardiac Consultant of eResearchTechnology Inc (eRT), Philadelphia, PA, USA, which provides cardiac safety services to the drug development community. Both authors now provide expert consultancy services on the development of new drugs to a number of pharmaceutical companies.

The views expressed in this paper are those of the authors and do not necessarily reflect the views or opinions of their affiliates, any regulatory authorities or any of their advisory bodies.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dr Rashmi R. Shah.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shah, R.R., Morganroth, J. Early Investigation of QTc Liability. Drug Saf 35, 695–709 (2012). https://doi.org/10.1007/BF03261967

Download citation

Keywords

  • Maximum Tolerate Dose
  • Moxifloxacin
  • Sparfloxacin
  • Cardiac Repolarization
  • Supratherapeutic Dose