Skip to main content

Advertisement

SpringerLink
Log in

Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study.

Methods

The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure–response (ER) analysis. Results from the two studies were compared.

Results

In both studies, moxifloxacin effect established assay sensitivity. IUT analysis revealed comparable pitolisant-induced maximum mean (90 % confidence interval (CI)) placebo-corrected increase from baseline (ΔΔQTcF) in both the studies, being 13.3 (8.1; 18.5) ms at 200-mg and 9.9 (4.7; 15.1) ms at 240-mg doses in SAD study and 5.27 (2.35; 8.20) ms at 120-mg dose in TQT study. ER analysis revealed that ER slopes in SAD and TQT studies were comparable and significantly positive (0.031 vs 0.027 ms/ng/mL, respectively). At geometric mean concentrations, bootstrap predicted ΔΔQTcF (90 % CI) were 9.23 (4.68; 14.4) ms at 279 ng/mL (240-mg dose) in the SAD study and 4.97 (3.42; 8.19) ms at 156 ng/mL (120-mg dose) in the TQT study.

Conclusion

Pitolisant lacked an effect of regulatory concern on QTc interval in both the studies, however analysed, suggesting that the results from the SAD study could have mitigated the need for a TQT study. Our findings add to the growing evidence that intensive ECG monitoring in early phase clinical studies can replace a TQT study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Committee for Medicinal Products for Human Use (CHMP). 2015 ICH E14 Note for Guidance on: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs (CHMP/ICH/2/04) (ICH E14). European Medicines Agency, London, November 2005. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002879.pdf [Accessed on 15 May 2015]

  2. Committee for Medicinal Products for Human Use (CHMP) 2016 ICH Topic E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Questions and Answers (EMA/CHMP/ICH/310133/2008). European Medicines Agency, London, May 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002878.pdf [Accessed on 15 May 2015]

  3. ICH E14 Implementation Working Group 2014 ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Questions & Answers (R2). International Conference on Harmonisation, Geneva, March 2014. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_QAs_R2_Step4.pdf [Accessed on 15 May 2015]

  4. Committee for Medicinal Products for Human Use (CHMP) 2017 Withdrawal Assessment Report for Garenoxacin Masylate (EMEA/H/C/747). (Document Reference EMEA/CHMP/363573/2007). European Medicines Agency, London, October 2007 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/01/WC500067888.pdf [Accessed 26 May 2015]

  5. Wang Z, DM G, Krishna G (2007) Retrospective analysis of electrocardiographic changes after administration of oral or intravenous garenoxacin in five phase I, placebo-controlled studies in healthy volunteers. Clin Ther 29:1098–1106

    Article  CAS  PubMed  Google Scholar 

  6. 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 91:281–288

    Article  CAS  PubMed  Google Scholar 

  7. Sager PT, Gintant G, Turner JR, Pettit S, Stockbridge N (2014) Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium. Am Heart J 167:292–300

    Article  PubMed  Google Scholar 

  8. Shah RR, Morganroth J (2012) Early investigation of QTc liability: the role of multiple ascending dose (MAD) study. Drug Saf 35:695–709

    Article  CAS  PubMed  Google Scholar 

  9. Darpo B, Garnett C, Benson CT, et al. (2014) Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward. Am Heart J 168:262–272

    Article  PubMed  Google Scholar 

  10. Ferber G, Zhou M, Darpo B (2015) Detection of QTc effects in small studies - Implications for replacing the thorough QT study. Ann Noninvasive Electrocardiol 20:368–377

    Article  PubMed  Google Scholar 

  11. Zhang J, Chen H, Tsong Y, Stockbridge N (2015) Lessons learned from hundreds of thorough QT studies. Ther Innov Reg Sci 49:392–397

    Google Scholar 

  12. Darpo B, Garnett C (2013) Early QT assessment - how can our confidence in the data be improved? Br J Clin Pharmacol 76:642–648

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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 48:13–18

    Article  CAS  PubMed  Google Scholar 

  14. Lee JY, Garnett CE, Gobburu JV, et al. (2011) Impact of pharmacometric analyses on new drug approval and labelling decisions: a review of 198 submissions between 2000 and 2008. Clin Pharmacokinet 50:627–635

    Article  PubMed  Google Scholar 

  15. Jönsson S, Henningsson A, Edholm M, Salmonson T (2011) Contribution of modeling and simulation studies in the regulatory review: a European regulatory perspective. In: Kimko H, Peck C (eds) Clinical Trial Simulations: Applications and Trends. Springer Science pp, New York, pp. 15–36

    Chapter  Google Scholar 

  16. Garnett CE, Lee JY, Gobburu JVS (2011) Contribution of modelling and simulation in the regulatory review and decision-making: U.S. FDA perspective. In: Kimko H, Peck C (eds) Clinical Trial Simulations: Applications and Trends. Springer Science, New York, pp. 37–57

    Chapter  Google Scholar 

  17. Shah RR, Maison-Blanche P, Duvauchelle T, Robert P, Denis E (2015) Establishing assay sensitivity in QT studies: Experience with the use of moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a thorough QT study. Eur J Clin Pharmacol 71:1451–1459

    Article  CAS  PubMed  Google Scholar 

  18. Ligneau X, Landais L, Perrin D, et al. (2007) Brain histamine and schizophrenia: potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649. Biochem Pharmacol 73:1215–1224

    Article  CAS  PubMed  Google Scholar 

  19. Schwartz JC (2011) The histamine H3-receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol 163:713–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Łazewska D, Kieć-Kononowicz K (2010) Recent advances in histamine H3-receptor antagonists/inverse agonists. Expert Opin Ther Pat 20:1147–1169

    Article  PubMed  Google Scholar 

  21. Dauvilliers Y, Bassetti C, Lammers GJ, et al. (2013) for HARMONY I study group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol 12:1068–1075

    Article  CAS  PubMed  Google Scholar 

  22. Committee for Medicinal Products for Human Use (CHMP) 2005 “Narcolepsy treatment recommended for approval” (EMA/CHMP/764032/2015). European Medicines Agency, London, November 2005. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/11/WC500196774.pdf [Accessed on 15 December 2015]

  23. Committee for Medicinal Products for Human Use (CHMP) (2011) Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2**). European Medicines Agency, London, July 2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf [Accessed on 15 May 2015]

  24. Darpo B, Benson C, Dota C, et al. (2015) Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase. Clin Pharmacol Ther 97:326–335

    Article  CAS  PubMed  Google Scholar 

  25. Eichenbaum G, Pugsley MK, Gallacher DJ, et al. (2012) Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti-MRSA fluoroquinolone JNJ-Q2. Br J Pharmacol 166:1694–1707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Garnett C 2016 Presentation to the Clinical Pharmacology Group. The International Consortium for Innovation and Quality in Pharmaceutical Development (3 May 2012).

  27. 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 142:427–435

    Article  CAS  PubMed  Google Scholar 

  28. 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 172:4002–4011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nelson CH, Wang L, Fang L, et al. (2015) A quantitative framework to evaluate proarrhythmic risk in a first-in-human study to support waiver of a thorough QT study. Clin Pharmacol Ther 98(6):630–638.

    Article  CAS  PubMed  Google Scholar 

  30. Yang S, Beerahee M (2013) Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials. Eur J Clin Pharmacol 69:1261–1267

    Article  CAS  PubMed  Google Scholar 

  31. Barbour AM, Magee M, Shaddinger B, et al. (2015) Utility of concentration-effect modelling and simulation in a thorough QT study of losmapimod. J Clin Pharmacol 55:661–670

    Article  CAS  PubMed  Google Scholar 

  32. Shumaker RC, Zhou M, Ren M, et al. (2014) Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT study in healthy volunteers. Cancer Chemother Pharmacol 73:1109–1117

    Article  CAS  PubMed  Google Scholar 

  33. Food and drug Administration 2015 Label for LENVIMA (lenvatinib) (approved 13 February 2015). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf [Accessed on 20 May 2015]

  34. Zuo P, Haberer LJ, Fang L, Hunt TL, Ridgway D, Russo MW (2014) Integration of modelling and simulation to support changes to ondansetron dosing following a randomized, double-blind, placebo-, and active-controlled thorough QT study. J Clin Pharmacol 54:1221–1229

    Article  CAS  PubMed  Google Scholar 

  35. Florian JA, Tornøe CW, Brundage R, Parekh A, Garnett CE (2011) Population pharmacokinetic and concentration-QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies. J Clin Pharmacol 51:1152–1162

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The two studies were funded by BIOPROJET PHARMA, Paris (France). They were part of a dossier for regulatory submission for a marketing authorization. The ER modelling was performed by Mathieu Felices, Pharmacometrician, PhinC Development, Évry (France).

Author’s Contributions

The innovative design of the SAD study was conceived and set up by TD.

Both studies were carried out under the direction of TD and PM-B.

Analytical method development, validation and bioanalysis were performed by ED and PR.

Pharmacokinetic analysis was performed and interpreted by PR.

Both studies were analysed and interpreted by RRS, PM-B and TD.

The concept of this comparison was conceived by PM-B and RRS.

The first draft of the manuscript was prepared by RRS.

Subsequent drafts were revised by RRS, PM-B, TD, PR and ED.

The final version for submission was approved by RRS, PM-B, TD, PR and ED.

Author information

Authors and Affiliations

  1. 8 Birchdale, Gerrards Cross, SL9 7JA, UK

    Rashmi R. Shah

  2. Hôpital Bichat, Paris, France

    Pierre Maison-Blanche

  3. Bioprojet Biotech, Saint Gregoire, France

    Philippe Robert & Emmanuel Denis

  4. Bioprojet Pharma, Paris, France

    Thierry Duvauchelle

Authors
  1. Rashmi R. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Maison-Blanche
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philippe Robert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emmanuel Denis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thierry Duvauchelle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rashmi R. Shah.

Ethics declarations

All procedures performed in the two studies were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of interest

RRS, PM-B and TD are paid consultants to BIOPROJET and PR and ED are paid employees of BIOPROJET. PM-B is also a consultant to CARDIABASE, the centralized laboratory that analysed the ECGs from the two studies. The authors declare that they have no conflict of interest. The funding sources did not influence design and conduct of the study; collection, management, analysis, and interpretation of the data and preparation, review, or approval of the manuscript.

Electronic supplementary material

ESM 1

(DOC 65 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shah, R.R., Maison-Blanche, P., Robert, P. et al. Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist. Eur J Clin Pharmacol 72, 533–543 (2016). https://doi.org/10.1007/s00228-016-2023-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-016-2023-3

Keywords

Search

Navigation