Early investigation of qtc liability: The role of multiple ascending dose (MAD) study

Drug Safety

Volumn 35, Issue 9, 2012, Pages 695-709

  Shah, Rashmi R ^a   Morganroth, Joel ^b  

^a Rashmi Shah Consultancy Ltd   (United Kingdom)

^b eResearchTechnology   (United States)

Author keywords

Citalopram; Dextropropoxyphene; Moxifloxacin; Pharmacokinetic pharmacodynamic relationships; QT interval prolongation; Sparfloxacin

Indexed keywords

ASTEMIZOLE; CITALOPRAM; DEXTROPROPOXYPHENE; DRUG METABOLITE; HALOFANTRINE; MOXIFLOXACIN; NORPROPOXYPHENE; PLACEBO; SERTINDOLE; SPARFLOXACIN;

BLOOD SAMPLING; CLINICAL DECISION MAKING; CLINICAL PROTOCOL; CLINICAL STUDY; CONFERENCE PAPER; CORRECTED QT INTERVAL; DOSE RESPONSE; DRUG DETERMINATION; DRUG DEVELOPMENT; DRUG DOSE; DRUG DOSE ESCALATION; DRUG DOSE SEQUENCE; DRUG DOSE TITRATION; ELECTROCARDIOGRAPHY; ELECTROCARDIOGRAPHY MONITORING; HEART RATE; HUMAN; LOADING DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MULTIPLE ASCENDING DOSE; MULTIPLE DRUG DOSE; PHARMACODYNAMICS; PHARMACOKINETICS; PHOTOTOXICITY; PRIORITY JOURNAL; QT INTERVAL; QT PROLONGATION; RECOMMENDED DRUG DOSE; RISK BENEFIT ANALYSIS; SIDE EFFECT; SINGLE DRUG DOSE; SUPRATHERAPEUTIC DOSE; TIME TO MAXIMUM PLASMA CONCENTRATION;

CARDIOVASCULAR SYSTEM; CLINICAL TRIALS AS TOPIC; DOUBLE-BLIND METHOD; DRUGS, INVESTIGATIONAL; ELECTROCARDIOGRAPHY; HUMANS; INTERNATIONAL COOPERATION; LONG QT SYNDROME; MAXIMUM TOLERATED DOSE; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84864965082     PISSN: 01145916     EISSN: 11791942     Source Type: Journal    
DOI: 10.2165/11634810-000000000-00000     Document Type: Conference Paper

References (47)

1. Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol 2002; 54: 188-202 (Pubitemid 35024944)
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
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. 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/WC 500002841.pdf [Accessed 2012 Jan 26]
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. 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. Shah RR. Drugs, QT interval prolongation and ICH E14: the need to get it right. Drug Saf 2005; 28: 115-25 (Pubitemid 40321767)
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
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
10. Malik M, Garnett CE, Zhang J. Thorough QT Studies: questions and quandaries. Drug Saf 2010; 33: 1-14
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
12. Morganroth J. Cardiac repolarization and the safety of new drugs defined by electrocardiography. Clin Pharmacol Ther 2007; 81: 108-13 (Pubitemid 46050875)
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 (Pubitemid 34587799)
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
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 (Pubitemid 350292272)
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 (Pubitemid 34177674)
17. Batchvarov VN, Ghuran A, Smetana P, et al. QT-RR relationship in healthy subjects exhibits substantial intersubject variability and high intrasubject stability. Am J Physiol Heart Circ Physiol 2002; 282: H2356-63 (Pubitemid 34663047)
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 (Pubitemid 38758763)
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 (Pubitemid 34214594)
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 (Pubitemid 41132697)
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
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: implication for the assessment of drug effect on the QT interval. Ann Noninvasive Electrocardiol 2005; 10: 169-78 (Pubitemid 40646658)
23. Yan LK, Zhang J, Ng MJ, et al. Statistical characteristics of moxifloxacin-induced QTc effect. J Biopharm Stat 2010; 20: 497-507
24. Zhang J. Testing for positive control activity in a thorough QTc study. J Biopharm Stat 2008; 18: 517-28 (Pubitemid 351891688)
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 (Pubitemid 26385262)
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 (Pubitemid 28531598)
27. Abernethy DR, Wesche DL, Barbey JT, et al. Stereoselective halofantrine disposition and effect: concentrationrelated QTc prolongation. Br J Clin Pharmacol 2001; 51: 231-7 (Pubitemid 32391500)
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
29. Morganroth J. Response to "Design of the 'thorough QT study"'. Clin Pharmacol Ther 2008; 83: 529-30
30. Zhang J, Stockbridge N. Selection of the time points for a thorough QTc study. Drug Inform J 2011; 45: 713-5
31. Darpo B, Sager P. Design of the "thorough QT study". Clin Pharmacol Ther 2008; 83: 528-9
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
33. Tyl B, Kabbaj M, Fassi B, et al. Comparison of semiautomated and fully automated methods for QT measurement during a thorough QT/QTc study: variability and sample size considerations. J Clin Pharmacol 2009; 49: 905-15
34. Rawlins MD. Cutting the cost of drug development? Nat Rev Drug Discov 2004; 3: 360-4 (Pubitemid 38499763)
35. Bouvy JC, Koopmanschap MA, Shah RR, et al. The costeffectiveness of drug regulation: the example of thorough QT/QTc studies. Clin Pharmacol Ther 2012; 91: 281-8
36. ClinicalTrials.gov, a service of the US National Institutes of Health [online]. Available from URL: http://clinialtrials. gov [Accessed 2012 Mar 10]
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 (Pubitemid 29291440)
38. Morganroth J, Hunt T, Dorr MB, et al. The cardiac pharmacodynamics of therapeutic doses of sparfloxacin. Clin Ther 1999; 21: 1171-81 (Pubitemid 29380472)
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.access data.fda.gov/drugsatfda-docs/nda/2011/ 020822Orig1s038s040-021046Orig1s016s017Rev.pdf [Accessed 2012 Jan 26]
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
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
42. Zhang J. Novel approaches to TQT study design and analysis. A presentation at the 3rd DIA Cardiac Safety Workshop; 2012 May 28-29; Tokyo
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
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 (Pubitemid 30012060)
45. Shah RR, Morganroth J. Evaluating the QT-liability of a drug during its development. Pharm Med 2008; 22: 151-64 (Pubitemid 351747759)
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
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/Post marketDrugSafetyInformationforPatientsandProviders/UCM234330.pdf [Accessed 2012 Mar 4]