The Proarrhythmic Cardiac Safety Regulatory Landscape Circa 2005–2015: Drug-Induced hERG Channel Block and the Thorough QT/QTc Study

  • J. Rick Turner
  • Dilip R. Karnad
  • Snehal Kothari
Chapter

Abstract

The first step in the field of proarrhythmic cardiac safety is to determine to the greatest degree possible during nonclinical and preapproval clinical development whether a noncardiac drug has the propensity to lead to the polymorphic ventricular dysrhythmia torsades (Dessertenne 1966) in patients who may be prescribed the drug should it subsequently be approved for marketing. The second step is to remain alert to unexpected cardiac adverse drug reactions during its therapeutic use. This chapter’s focus is the first step.

References

  1. Albertson TE, Dean NC, El Solh AA et al (2010) Fluoroquinolones in the management of community-acquired pneumonia. Int J Clin Pract 64:378–388PubMedCrossRefGoogle Scholar
  2. Bass AS, Darpo B, Breidenbach A et al (2008) International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes. Br J Pharmacol 154:1491–1501PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bloomfield DM (2015) Incorporating exposure-response modeling into the assessment of QTc interval: a potential alternative to the thorough QT study. Clin Pharmacol Ther 97:444–446PubMedCrossRefGoogle Scholar
  4. Bouvy JC, Koopmanschap MA, Shah RR, Schellekens H (2012) The cost-effectiveness of drug regulation: the example of thorough QT/QTc studies. Clin Pharmacol Ther 91:281–288PubMedCrossRefGoogle Scholar
  5. Brown AM (2005) hERG block, QT liability and sudden cardiac death. In: Chadwick DJ, Goode J (eds) The hERG potassium channel: structure, function, and long QT syndrome. Wiley, Chichester, pp 118–131CrossRefGoogle Scholar
  6. Burkhardt O, Welte T (2009) 10 years’ experience with the pneumococcal quinolone moxifloxacin. Expert Rev Anti Infect Ther 7:645–668PubMedCrossRefGoogle Scholar
  7. Camm AJ, Malik M, Yap YG (2004) Acquired long QT syndrome. Future/Blackwell Publishing, MaldenCrossRefGoogle Scholar
  8. Chuchalin A, Zakharova M, Dokic D et al (2013) Efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis: a prospective, multicenter, observational study (AVANTI). BMC Pulm Med 13:5PubMedPubMedCentralCrossRefGoogle Scholar
  9. Couderc JP, Garnett C, Li M et al (2011) Highly automated QT measurement techniques in 7 thorough QT studies implemented under ICH E14 guidelines. Ann Noninvasive Electrocardiol 16:13–24PubMedPubMedCentralCrossRefGoogle Scholar
  10. de Ponti F (2008) Pharmacological and regulatory aspects of QT prolongation. In: Vaz JR, Klabunde T (eds) Antitargets: prediction and prevention of drug side effects. Wiley-VCH, WeinheimGoogle Scholar
  11. Dessertenne F (1966) La tachycardia ventriculaire a deux foyers opposees variable. Arch Mal Coeur Vaiss 59:263–272PubMedGoogle Scholar
  12. EMEA (1997) Non-clinical: pharmacology. Points to consider on the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. December 1997. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000395.jsp&mid=WC0b01ac058002956d. Accessed 22 Nov 2015
  13. Fosser C, Duczynski G, Agin M, Wicker P, Darpo B (2009) Comparison of manual and automated measurements of the QT interval in healthy volunteers: an analysis of five thorough QT studies. Clin Pharmacol Ther 86:503–506PubMedCrossRefGoogle Scholar
  14. Garnett CE, Beasley N, Bhattaram VA et al (2008) Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 48:13–18PubMedCrossRefGoogle Scholar
  15. Garnett CE, Zhu H, Malik M et al (2012) Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am Heart J 163:912–930PubMedCrossRefGoogle Scholar
  16. Gellert KS, Rautaharju P, Snyder ML et al (2014) Short-term repeatability of electrocardiographic Tpeak-Tend and QT intervals. J Electrocardiol 47:356–361PubMedPubMedCentralCrossRefGoogle Scholar
  17. Greene T (2015) Randomized controlled trials 5: determining the sample size and power for clinical trials and cohort studies. Methods Mol Biol 1281:225–247PubMedCrossRefGoogle Scholar
  18. Hancox JC, McPate MJ, El Harchi A, Zhang YH (2008) The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther 119:118–132PubMedCrossRefGoogle Scholar
  19. Heijman J, Voigt N, Carlsson LG, Dobrev D (2014) Cardiac safety assays. Curr Opin Pharmacol 15:16–21PubMedCrossRefGoogle Scholar
  20. Hnatkova K, Gang Y, Batchvarov VN, Malik M (2006) Precision of QT interval measurement by advanced electrocardiographic equipment. Pacing Clin Electrophysiol 29:1277–1284PubMedCrossRefGoogle Scholar
  21. Hnatkova K, Kowalski D, Keirns JJ, van Gelderen EM, Malik M (2014) QTc changes after meal intake: sex differences and correlates. J Electrocardiol 47:856–862PubMedCrossRefGoogle Scholar
  22. ICH Guideline E14: Questions & Answers, third revision (2015). Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf. Accessed 29 Dec 2015
  23. Jia B, Lynn HS (2015) A sample size planning approach that considers both statistical significance and clinical significance. Trials 16:213PubMedPubMedCentralCrossRefGoogle Scholar
  24. Johannesen L, Vicente J, Gray RA et al (2014) Improving the assessment of heart toxicity for all new drugs through translational regulatory science. Clin Pharmacol Ther 95:501–508PubMedCrossRefGoogle Scholar
  25. Kannel WB, Sorlie P (1975) Hypertension in Framingham. In: Paul O (ed) Epidemiology and control of hypertension. Grune & Stratton/Intercontinental Medical Book Corporation, New YorkGoogle Scholar
  26. Kothari S, Karnad D, Panicker G, Turner JR (2015) Cardiac safety investigations 10 years after ICH Guidance E14: evolving industry and regulatory viewpoints on evaluation of proarrhythmic risk during new drug development. J Clin Stud 7(1):22–30Google Scholar
  27. Kuzman I, Bezlepko A, Kondova Topuzovska I et al (2014) Efficacy and safety of moxifloxacin in community acquired pneumonia: a prospective, multicenter, observational study (CAPRIVI). BMC Pulm Med 14:105PubMedPubMedCentralCrossRefGoogle Scholar
  28. Lagrutta AA, Salata JJ (2006) Ion channel safety issues in drug development. In: Triggle DJ, Gopalakrishnan M, Rampe D, Zheng W (eds) Voltage-gated ion channels as drug targets. Wiley-VCH, Manheim, pp 444–465CrossRefGoogle Scholar
  29. Lee J, Turner JR (2016) Raising the bar in renal sympathetic denervation research and reporting. J Clin Hypertens (Greenwich) 18:89–94CrossRefGoogle Scholar
  30. Leishman D, Waldron G (2006) Assay technologies: techniques available for quantifying drug-channel interactions. In: Triggle DJ, Gopalakrishnan M, Rampe D, Zheng W (eds) Voltage-gated ion channels as drug targets. Wiley-VCH, Manheim, pp 37–63CrossRefGoogle Scholar
  31. Link MG, Yan G-X, Kowey PR (2010) Evaluation of toxicity for heart failure therapeutics: studying effects on the QT interval. Circ Heart Fail 3:547–555PubMedCrossRefGoogle Scholar
  32. Litwin JS, Kleiman RB, Gussak I (2008) Acquired (drug-induced) long QT syndrome. In: Gussak I, Antzelevitch C (eds) Electrical diseases of the heart: genetics, mechanisms, treatment, and prevention. Springer, London, pp 705–718CrossRefGoogle Scholar
  33. Malik M, Camm AJ (2001) Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. Drug Saf 24:323–351PubMedCrossRefGoogle Scholar
  34. Malik M, Hnatkova K, Batchvarov V et al (2004) Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation. Pacing Clin Electrophysiol 27:1659–1669PubMedCrossRefGoogle Scholar
  35. Malik M, Hnatkova K, Ford J, Madge D (2008) Near-thorough QT study as part of a first-in-man study. J Clin Pharmacol 48:1146–1157PubMedCrossRefGoogle Scholar
  36. Mason JW (2008) Reduce the number of ECGs: definitive QT study design. Presentation given at the CBI second annual cardiac safety summit, Alexandria, 15 Jan 2008Google Scholar
  37. Mason JW, Moon TE (2015) Automated measurements for individualized heart rate correction of the QT interval. Clin Trials 12:149–155PubMedCrossRefGoogle Scholar
  38. Maury P, Sacher F, Gourraud JB et al (2015) Increased Tpeak-Tend interval is highly and independently related to arrhythmic events in Brugada syndrome. Heart Rhythm 12:2469–2476PubMedCrossRefGoogle Scholar
  39. Mayo NE (2009) Randomized trials and other parallel comparisons of treatment. In: Bailar JC III, Hoaglin DC (eds) Medical uses of statistics, 3rd edn. Wiley, Hoboken, pp 51–89Google Scholar
  40. Min SS, Turner JR, Nada A et al (2010) Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development. Am Heart J 159:716–729PubMedCrossRefGoogle Scholar
  41. Morganroth J (2005) Design and conduct of the through phase I ECG trial for new bioactive drugs. In: Morganroth J, Gussak I (eds) Cardiac safety of noncardiac drugs: practical guidelines for clinical research and drug development. Humana Press Inc., Totowa, pp 205–222CrossRefGoogle Scholar
  42. Panicker GK, Karnad DR, Joshi R et al (2009) Z-score for benchmarking reader competence in a central ECG laboratory. Ann Noninvasive Electrocardiol 14:19–25PubMedCrossRefGoogle Scholar
  43. Panicker GK, Salvi V, Karnad DR et al (2010) Automated QT interval measurement in Holter ECGs recorded at 180 and 1000 samples/second. Computing in Cardiology 37:761–764Google Scholar
  44. Redfern WS, Carlsson L, Davis AS 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. Cardiovasc Res 58:32–45PubMedCrossRefGoogle Scholar
  45. Redfern WS, Bialecki R, Ewart L et al (2010) Impact and prevalence of safety pharmacology-related toxicities throughout the pharmaceutical life cycle. J Pharmacol Toxicol Methods 62:e29CrossRefGoogle Scholar
  46. Rodriguez I, Erdman A, Padhi D et al (2010) Electrocardiographic assessment for therapeutic proteins: scientific discussion. Am Heart J 160:627–634PubMedCrossRefGoogle Scholar
  47. Rock EP, Finkle J, Fingert HJ et al (2009) Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J 157:827–836, 836.e1PubMedCrossRefGoogle Scholar
  48. Salvi V, Karnad DR, Panicker GK, Kothari S (2010) Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development. Br J Pharmacol 159:34–48PubMedCrossRefGoogle Scholar
  49. Salvi V, Karnad DR, Kerkar V et al (2014) Comparison of two methods of estimating reader variability in QT interval measurements in thorough QT/QTc studies. Ann Noninvasive Electrocardiol 19:182–189PubMedCrossRefGoogle Scholar
  50. Sano M, Aizawa Y, Katsumata Y et al (2014) Evaluation of differences in automated QT/QTc measurements between Fukuda Denshi and Nihon Koden systems. PLoS One 9:e106947PubMedPubMedCentralCrossRefGoogle Scholar
  51. Satin LZ, Durham TA, Turner JR (2011) Assessing a drug’s proarrhythmic liability: an overview of computer simulation modeling, nonclinical assays, and the thorough QT/QTc Study. Drug Inf J 45:357–375CrossRefGoogle Scholar
  52. Shah RR (2005) Interpretation of clinical ECG data: understanding the risk from non-anti-arrhythmic drugs. In: Morganroth JM, Gussak I (eds) Cardiac safety of noncardiac drugs: practical guidelines for clinical research and drug development. Humana Press Inc., Totowa, pp 259–298CrossRefGoogle Scholar
  53. Taubel J, Naseem A, Harada T et al (2010) Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers. Br J Clin Pharmacol 69:391–400PubMedPubMedCentralCrossRefGoogle Scholar
  54. Taubel J, Wong AH, Naseem A, Ferber G, Camm AJ (2012) Shortening of the QT interval after food can be used to demonstrate assay sensitivity in thorough QT studies. J Clin Pharmacol 52:1558–1565PubMedCrossRefGoogle Scholar
  55. Teare MD, Dimairo M, Shephard N et al (2014) Sample size requirements to estimate key design parameters from external pilot randomised controlled trials: a simulation study. Trials 15:264PubMedPubMedCentralCrossRefGoogle Scholar
  56. Tisdale JE, Kovacs R, Mi D et al (2007) Accuracy of uncorrected versus corrected QT interval for prediction of torsade de pointes associated with intravenous haloperidol. Pharmacotherapy 27:175–182PubMedCrossRefGoogle Scholar
  57. Tulkens PM, Arvis P, Kruesmann F (2012) Moxifloxacin safety: an analysis of 14 years of clinical data. Drugs R D 12:71–100PubMedPubMedCentralCrossRefGoogle Scholar
  58. Turner JR (2010) New drug development: an introduction to clinical trials, 2nd edn. Springer, New YorkGoogle Scholar
  59. Turner JR, Durham TA (2009) Integrated cardiac safety: assessment methodologies for noncardiac drugs in discovery, development, and postmarketing surveillance. Wiley, HobokenGoogle Scholar
  60. Turner JR, Kothari K, Cabell CH et al (2013) Fifteen years of cardiac safety: history, state-of-the-science research, and glimpses into the future. Int Pharm Ind 5(1):110–119Google Scholar
  61. Turner JR, Panicker GK, Karnad DR et al (2014) Cardiovascular safety monitoring during oncology drug development and therapy. Am J Ther 21:512–522PubMedCrossRefGoogle Scholar
  62. Turner JR, Britto M, Cabell CH et al (2015) Evolution of the proarrhythmic cardiac safety regulatory landscape: the likely revision of ICH Guideline E14 and its consequences. J Clin Stud 7(6):52–58Google Scholar
  63. Valentin JP (2010) Reducing QT, liability and proarrhythmic risk in drug discovery and development. Br J Pharmacol 159:5–11PubMedPubMedCentralCrossRefGoogle Scholar
  64. Vicente J, Johannesen L, Mason JW et al (2015) Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil. J Am Heart Assoc 4:pii:e001615Google Scholar
  65. Yan LK, Zhang J, Ng MJ, Dang Q (2010) Statistical characteristics of moxifloxacin-induced QTc effect. J Biopharm Stat 20:497–507PubMedCrossRefGoogle Scholar
  66. Zhang J (2011) Optimal sample size allocation in a thorough QTc study. Drug Inf J 45:455–468CrossRefGoogle Scholar
  67. Zhang J, Machado SG (2008) Statistical issues including design and sample size calculation in thorough QT/QTc studies. J Biopharm Stat 18:451–467PubMedCrossRefGoogle Scholar
  68. Zhang J, Stockbridge N (2011) Selection of the time points for a thorough QTc study. Drug Inf J 45:713–715CrossRefGoogle Scholar
  69. Zhang J, Chen H, Tsong Y, Stockbridge N (2015) Lessons learned from hundreds of thorough TQ studies. Ther Innov Regul Sci 49:392–397CrossRefGoogle Scholar

Further Reading

  1. Aban IB, George B (2015) Statistical considerations for preclinical studies. Exp Neurol 270:82–87PubMedPubMedCentralCrossRefGoogle Scholar
  2. Adar L, Avisar N, Lammerich A, Kleiman RB, Spiegelstein O (2015) A thorough QT study to assess the effects of tbo-filgrastim on cardiac repolarization in healthy subjects. Drug Des Devel Ther 9:2653–2662PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bass AS, Vargas HM, Valentin JP et al (2011) Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society. J Pharmacol Toxicol Methods 64:7–15PubMedCrossRefGoogle Scholar
  4. Berridge BR, Hoffmann P, Turk JR et al (2013) Integrated and translational nonclinical in vivo cardiovascular risk assessment: gaps and opportunities. Regul Toxicol Pharmacol 65:38–46PubMedCrossRefGoogle Scholar
  5. Berman CL, Cannon K, Cui Y et al (2014) Recommendations for safety pharmacology evaluations of oligonucleotide-based therapeutics. Nucleic Acid Ther 24:291–301PubMedCrossRefGoogle Scholar
  6. Blanchard OL, Smoliga JM (2015) Translating dosages from animal models to human clinical trials-revisiting body surface area scaling. FASEB J 29:1629–1634PubMedCrossRefGoogle Scholar
  7. Cavero I (2014) 13th annual meeting of the safety pharmacology society: focus on novel technologies and safety pharmacology frontiers. Expert Opin Drug Saf 13:1271–1281PubMedCrossRefGoogle Scholar
  8. Chain AS, Dubois VF, Danhof M, Sturkenboom MC, Della Pasqua O, Cardiovascular Safety Project Team, TI Pharma PKPD Platform (2013) Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation. Br J Clin Pharmacol 76:708–724PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chen Q, Liu YM, Liu Y et al (2015) Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized, single-blind, crossover study. Acta Pharmacol Sin 36:448–453PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chuang-Stein C (1992) Summarizing laboratory data with different reference ranges in multi-center clinical trials. Drug Info J 26:77–84Google Scholar
  11. Chui RW, Derakhchan K, Vargas HM (2012) Comprehensive analysis of cardiac arrhythmias in telemetered cynomolgus monkeys over a 6 month period. J Pharmacol Toxicol Methods 66:84–91PubMedCrossRefGoogle Scholar
  12. Darpo B, Zhou M, Matthews J et al (2014) Albiglutide does not prolong QTc interval in healthy subjects: a Thorough ECG Study. Diab Ther 5:141–153CrossRefGoogle Scholar
  13. Dayan CM, Wraith DC (2008) Preparing for first-in-man studies: the challenges for translational immunology post-TGN1412. Clin Exp Immunol 151:231–234PubMedPubMedCentralCrossRefGoogle Scholar
  14. Davis AM (2016) Torsades de pointes: 50 years later, can we see it coming? Circ Arrhythm Electrophysiol 9:e003850PubMedCrossRefGoogle Scholar
  15. Davy M, Upward J, Arumugham T et al (2013) Cardiac repolarization with gabapentin enacarbil in a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults. Clin Ther 35:1964–1974PubMedCrossRefGoogle Scholar
  16. Derakhchan K, Chui RW, Stevens D, Gu W, Vargas HM (2014) Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry. Br J Pharmacol 171:509–522PubMedCrossRefGoogle Scholar
  17. Dong JQ, Salinger DH, Endres CJ et al (2011) Quantitative prediction of human pharmacokinetics for monoclonal antibodies: retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet 50:131–142PubMedCrossRefGoogle Scholar
  18. Dubois VF, Yu H, Danhof M, Della Pasqua O, Cardiovascular Safety Project Team, TI Pharma PKPD Platform (2015) Model-based evaluation of drug-induced QTc prolongation for compounds in early development. Br J Clin Pharmacol 79:148–161PubMedCrossRefGoogle Scholar
  19. Dunne MW, Zhou M, Darpo B (2015) A thorough QT study with dalbavancin: a novel lipoglycopeptide antibiotic for the treatment of acute bacterial skin and skin-structure infections. Int J Antimicrob Agents 45:393–398PubMedCrossRefGoogle Scholar
  20. Ewart L, Aylott M, Deurinck M et al (2014) The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative. Toxicol Sci 142:427–435PubMedCrossRefGoogle Scholar
  21. Finco D, Grimaldi C, Fort M et al (2014) Cytokine release assays: current practices and future directions. Cytokine 66:143–155PubMedCrossRefGoogle Scholar
  22. Galeotti L, van Dam PM, Johannesen L, Vicente J, Strauss DG (2015) Computer simulations to investigate the causes of T-wave notching. J Electrocardiol 48:927–932PubMedCrossRefGoogle Scholar
  23. Gintant G (2011) An evaluation of hERG current assay performance: translating preclinical safety studies to clinical QT prolongation. Pharmacol Ther 129:109–119PubMedCrossRefGoogle Scholar
  24. Hancox JC, Melgari D, Dempsey CE et al (2015) hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes. Ther Adv Drug Saf 6:177–179PubMedPubMedCentralCrossRefGoogle Scholar
  25. Heller S, Darpö B, Mitchell MI et al (2015) Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: a report from the Cardiac Safety Research Consortium. Am Heart J 170:23–35PubMedCrossRefGoogle Scholar
  26. Hoch M, Darpo B, Remenova T et al (2014) A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist. Drug Des Devel Ther 9:175–185PubMedPubMedCentralCrossRefGoogle Scholar
  27. Hofmann C, Banken L, Hahn M et al (2012) Evaluation of the effects of bitopertin (RG1678) on cardiac repolarization: a thorough corrected QT study in healthy male volunteers. Clin Ther 34:2061–2071PubMedCrossRefGoogle Scholar
  28. Horvath CJ, Milton MN (2009) The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event? Toxicol Pathol 37:372–283PubMedCrossRefGoogle Scholar
  29. Johannesen L, Vicente J, Mason JW et al (2014) Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin Pharmacol Ther 96:549–558PubMedCrossRefGoogle Scholar
  30. Johannesen L, Vicente J, Mason JW et al (2016) Late sodium current block for drug-induced long QT syndrome: results from a prospective clinical trial. Clin Pharmacol Ther 99:214–223PubMedCrossRefGoogle Scholar
  31. Klein SK, Redfern WS (2015) Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: conference report. J Pharmacol Toxicol Methods 76:1–6PubMedCrossRefGoogle Scholar
  32. Liu Z, Wang B, Ma Z, Zhou Y, Du L, Li M (2015) Fluorogenic probe for the human ether-a-go-go-related gene potassium channel imaging. Anal Chem 87:2550–2554PubMedPubMedCentralCrossRefGoogle Scholar
  33. Lowe PJ, Tannenbaum S, Wu K, Lloyd P, Sims J (2010) On setting the first dose in man: quantitating biotherapeutic drug-target binding through pharmacokinetic and pharmacodynamic models. Basic Clin Pharmacol Toxicol 106:195–209PubMedCrossRefGoogle Scholar
  34. Malik M, Johannesen L, Hnatkova K, Stockbridge N (2016) Universal correction for QT/RR hysteresis. Drug Saf 39:577–588Google Scholar
  35. Malik M, Hnatkova K, Kowalski D, Keirns JJ, van Gelderen EM (2013) QT/RR curvatures in healthy subjects: sex differences and covariates. Am J Physiol Heart Circ Physiol 305:H1798–H1806PubMedPubMedCentralCrossRefGoogle Scholar
  36. Mendzelevski B, Ausma J, Chanter DO et al (2012) Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study. Br J Clin Pharmacol 73:203–209PubMedPubMedCentralCrossRefGoogle Scholar
  37. Mendzelevski B, Sprenger CR, Spiegelstein O, Rabinovich-Guilatt L (2014) Cardiac safety of rasagiline, a selective monoamine oxidase type B inhibitor for the treatment of Parkinson’s disease: a thorough QT/QTc study. Int J Clin Pharmacol Ther 52:192–201PubMedCrossRefGoogle Scholar
  38. Miki T, Tobisawa T, Sato T et al (2014) Does glycemic control reverse dispersion of ventricular repolarization in type 2 diabetes? Cardiovasc Diabetol 13:125PubMedPubMedCentralCrossRefGoogle Scholar
  39. Morganroth J, Wang Y, Thorn M et al (2015) Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study. Br J Clin Pharmacol 80:446–459PubMedPubMedCentralCrossRefGoogle Scholar
  40. Niemeijer MN, van den Berg ME, Eijgelsheim M, Rijnbeek PR, Stricker BH (2015) Pharmacogenetics of drug-induced QT interval prolongation: an update. Drug Saf 38:855–867PubMedPubMedCentralCrossRefGoogle Scholar
  41. Pallardy M, Hünig T (2010) Primate testing of TGN1412: right target, wrong cell. Br J Pharmacol 161:509–511PubMedPubMedCentralCrossRefGoogle Scholar
  42. Parkinson J, Visser SA, Jarvis P et al (2013) Translational pharmacokinetic-pharmacodynamic modeling of QTc effects in dog and human. J Pharmacol Toxicol Methods 68:357–366PubMedCrossRefGoogle Scholar
  43. Pierson JB, Berridge BR, Brooks MB et al (2013) A public-private consortium advances cardiac safety evaluation: achievements of the HESI Cardiac Safety Technical Committee. J Pharmacol Toxicol Methods 68:7–12PubMedCrossRefGoogle Scholar
  44. Polak S, Pugsley MK, Stockbridge N, Garnett C, Wiśniowska B (2015) Early drug discovery prediction of proarrhythmia potential and its covariates. AAPS J 17:1025–1032PubMedPubMedCentralCrossRefGoogle Scholar
  45. Prokscha S (2007) Practical guide to clinical data management, 2nd Edition. Taylor & Francis, Boca Raton.Google Scholar
  46. Pugsley MK, Curtis MJ (2012) Methodological innovations expand the safety pharmacology horizon. J Pharmacol Toxicol Methods 66:59–62PubMedCrossRefGoogle Scholar
  47. Rabkin SW, Cheng XB (2015) Nomenclature, categorization and usage of formulae to adjust QT interval for heart rate. World J Cardiol 7:315–325PubMedPubMedCentralCrossRefGoogle Scholar
  48. Ring A, Port A, Graefe-Mody EU et al (2011) The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses. Br J Clin Pharmacol 72:39–50PubMedPubMedCentralCrossRefGoogle Scholar
  49. Spyker DA, Voloshko P, Heyman ER, Cassella JV (2014) Loxapine delivered as a thermally generated aerosol does not prolong QTc in a thorough QT/QTc study in healthy subjects. J Clin Pharmacol 54:665–674PubMedCrossRefGoogle Scholar
  50. Stebbings R, Eastwood D, Poole S, Thorpe R (2013) After TGN1412: recent developments in cytokine release assays. J Immunotoxicol 10:75–82PubMedCrossRefGoogle Scholar
  51. Stockbridge N, Zhang J, Garnett C, Malik M (2012) Practice and challenges of thorough QT studies. J Electrocardiol 45:582–587PubMedCrossRefGoogle Scholar
  52. Taubel J, Ferber G, Lorch U et al (2014) Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects. Br J Clin Pharmacol 77:170–179PubMedCrossRefGoogle Scholar
  53. Thertulien R, Manikhas GM, Dirix LY et al (2012) Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol 69:341–350PubMedCrossRefGoogle Scholar
  54. Trepakova ES, Koerner J, Pettit SD, Valentin JP, HESI Pro-Arrhythmia Committee (2009) A HESI consortium approach to assess the human predictive value of non-clinical repolarization assays. J Pharmacol Toxicol Methods 60:45–50PubMedCrossRefGoogle Scholar
  55. Vargas HM, Amouzadeh HR, Engwall MJ (2013) Nonclinical strategy considerations for safety pharmacology: evaluation of biopharmaceuticals. Expert Opin Drug Saf 12:91–102PubMedCrossRefGoogle Scholar
  56. Vargas HM, Bass AS, Koerner J et al (2015) Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance. Br J Pharmacol 172:4002–4011PubMedPubMedCentralCrossRefGoogle Scholar
  57. Varkevisser R, Houtman MJ, Linder T et al (2013) Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue. Br J Pharmacol 169:1322–1334PubMedPubMedCentralCrossRefGoogle Scholar
  58. Vicente J, Johannesen L, Mason JW et al (2015) Sex differences in drug-induced changes in ventricular repolarization. J Electrocardiol 48:1081–1087PubMedCrossRefGoogle Scholar
  59. Vicente J, Simlund J, Johannesen L et al (2015) Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk. J Electrocardiol 48:533–538PubMedCrossRefGoogle Scholar
  60. Vugmeyster Y, Xu X, Theil FP, Khawli LA, Leach MW (2012) Pharmacokinetics and toxicology of therapeutic proteins: advances and challenges. World J Biol Chem 3:73–92PubMedPubMedCentralCrossRefGoogle Scholar
  61. Williamson D (2014) Approaches to modelling the human immune response in transition of candidates from research to development. J Immunol Res 2014:395302PubMedPubMedCentralCrossRefGoogle Scholar
  62. Yao X, Anderson DL, Ross SA et al (2008) Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model. Br J Pharmacol 154:1446–1456PubMedPubMedCentralCrossRefGoogle Scholar
  63. Yu Z, Klaasse E, Heitman LH, Ijzerman AP (2014) Allosteric modulators of the hERG K(+) channel: radioligand binding assays reveal allosteric characteristics of dofetilide analogs. Toxicol Appl Pharmacol 274:78–86PubMedCrossRefGoogle Scholar
  64. Yu Z, Jzerman AP, Heitman LH (2015) Kv 11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv 11.1 (hERG) inhibitors. Br J Pharmacol 172:940–955PubMedCrossRefGoogle Scholar
  65. Zhang KP, Yang BF, Li BX (2014) Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects. Acta Pharmacol Sin 35:1473–1484PubMedPubMedCentralCrossRefGoogle Scholar
  66. Zhang W, Smulders R, Abeyratne A et al (2013) Ipragliflozin does not prolong QTc interval in healthy male and female subjects: a phase I study. Clin Ther 35:1150–1161.e3PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • J. Rick Turner
    • 1
  • Dilip R. Karnad
    • 2
  • Snehal Kothari
    • 3
  1. 1.Cardiac Safety Services QuintilesDurhamUSA
  2. 2.Research TeamCardiac Safety Services QuintilesMumbaiIndia
  3. 3.Cardiac Safety Services Global HeadCardiac Safety Center of Excellence QuintilesMumbaiIndia

Personalised recommendations