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An Innovative Pharmacometric Approach for the Simultaneous Analysis of Frequency, Duration and Severity of Migraine Events

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Abstract

Purpose

To explore the use of a multistate repeated, time-to-categorical event model describing the frequency, severity and duration of migraines.

Methods

Subject level data from patients in placebo arms from two efficacy trials for migraine-preventive treatments were used. Models were developed using NONMEM 7.3. A survival model was combined with an ordered categorical model to form the repeated-time-to-start of categorical migraine event model, which simultaneously described the time-to-start of migraines and the severity of the starting migraine event. This was linked to a repeated-time-to-end of migraine event model with different hazard functions depending on the severity of the ongoing migraine event. Model performance was internally and externally qualified.

Results

The successfully qualified model showed that patients responding to placebo had a reduction in migraine incidence rate, and a decreased proportion of severe migraines. There was an increase in moderate migraine duration, an increased proportion of mild migraines and a reduction in proportion of severe migraines. Age was related to migraine duration.

Conclusions

The model represents an innovative framework for clinical trial modeling and simulation, and successfully describes placebo effect in migraine prevention. This approach can be adapted to investigate exposure-response relationship of drugs and can also be implemented in other therapeutic areas where the rate, duration and severity of disease episodes are relevant to trial outcomes.

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Abbreviations

RTTCE:

Repeated time-to-categorical event

VPC:

Visual predictive check

References

  1. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the global burden of Disease study 2015. Lancet. 2016;388(10053):1545–602.

    Article  Google Scholar 

  2. Hawkins K, Wang S, Rupnow M. Direct cost burden among insured US employees with migraine. Headache. 2008;48(4):553–63.

    Article  PubMed  Google Scholar 

  3. Headache Classification Committee of the International Headache S. The international classification of headache disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808.

    Article  Google Scholar 

  4. Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American migraine Prevalence and prevention (AMPP) study. Headache. 2013;53(8):1278–99.

  5. Charles A. Migraine. N Engl J Med. 2017;377(17):1698–9.

    Article  PubMed  Google Scholar 

  6. Yuan H, White CS, Silberstein SD. Calcitonin gene-related peptide antagonists in the treatment of episodic migraine. Clin Pharmacol Ther. 2019;105(5):1121–9.

    Article  CAS  PubMed  Google Scholar 

  7. Urits I, Jones MR, Gress K, Charipova K, Fiocchi J, Kaye AD, et al. CGRP antagonists for the treatment of chronic migraines: a comprehensive review. Curr Pain Headache Rep. 2019;23(5):29.

  8. Guidance for Industry. Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. In: USFaD A, editor. ; 1998.

    Google Scholar 

  9. Workgroup EM, Marshall SF, Burghaus R, Cosson V, Cheung SY, Chenel M, et al. Good practices in model-informed drug discovery and development: practice, application, and documentation. CPT Pharmacometrics Syst Pharmacol. 2016;5(3):93–122.

  10. Nguyen TH, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC, et al. Model evaluation Group of the International Society of Pharmacometrics best practice C. model evaluation of continuous data Pharmacometric models: metrics and graphics. CPT Pharmacometrics Syst Pharmacol. 2017;6(2):87–109.

  11. Holford N. A time to event tutorial for pharmacometricians. CPT Pharmacometrics Syst Pharmacol. 2013;2:e43.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Plan EL. Modeling and simulation of count data. CPT Pharmacometrics Syst Pharmacol. 2014;3:e129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Staab A, Tillmann C, Forgue ST, Mackie A, Allerheiligen SR, Rapado J, et al. Population dose-response model for tadalafil in the treatment of male erectile dysfunction. Pharm Res. 2004;21(8):1463–70.

  14. Schindler E, Karlsson MO. A minimal continuous-time Markov Pharmacometric model. AAPS J. 2017;19(5):1424–35.

    Article  CAS  PubMed  Google Scholar 

  15. Ueckert S. Modeling composite assessment data using item response theory. CPT Pharmacometrics Syst Pharmacol. 2018;7(4):205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bjornsson MA, Simonsson US. Modelling of pain intensity and informative dropout in a dental pain model after naproxcinod, naproxen and placebo administration. Br J Clin Pharmacol. 2011;71(6):899–906.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hu C, Sale ME. A joint model for nonlinear longitudinal data with informative dropout. J Pharmacokinet Pharmacodyn. 2003;30(1):83–103.

    Article  PubMed  Google Scholar 

  18. Pilla Reddy V, Kozielska M, Johnson M, Mafirakureva N, Vermeulen A, Liu J, et al. Population pharmacokinetic-pharmacodynamic modeling of haloperidol in patients with schizophrenia using positive and negative syndrome rating scale. J Clin Psychopharmacol. 2013;33(6):731–9.

  19. Plan EL, Karlsson KE, Karlsson MO. Approaches to simultaneous analysis of frequency and severity of symptoms. Clin Pharmacol Ther. 2010;88(2):255–9.

    Article  CAS  PubMed  Google Scholar 

  20. Beal SS LB.; Boeckmann, A.; Bauer, RJ. NONMEM user’s guide (1989–2009). In.; 2009.

  21. Lindbom L, Pihlgren P, Jonsson EN. PsN-toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Prog Biomed. 2005;79(3):241–57.

    Article  Google Scholar 

  22. Kelman L. Migraine changes with age: IMPACT on migraine classification. Headache. 2006;46(7):1161–71.

    Article  PubMed  Google Scholar 

  23. Perez-Pitarch A, Nock V, Huennemeyer A, Soleymanlou N, Kaspers S, Freijer J. Empagliflozin as Adjunct to Insulin in Patients with Type 1 Diabetes Mellitus: Modelling Rate and Severity of Hypoglycemic Events. In: PAGE meeting. Lisbon, Portugal; 2016.

    Google Scholar 

  24. Cox EH, Veyrat-Follet C, Beal SL, Fuseau E, Kenkare S, Sheiner LB. A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron. J Pharmacokinet Biopharm. 1999;27(6):625–44.

    Article  CAS  PubMed  Google Scholar 

  25. Juul RV, Rasmussen S, Kreilgaard M, Christrup LL, Simonsson US, Lund TM. Repeated time-to-event analysis of consecutive analgesic events in postoperative pain. Anesthesiology. 2015;123(6):1411–9.

    Article  CAS  PubMed  Google Scholar 

  26. Plan EL, Ma G, Nagard M, Jensen J, Karlsson MO. Transient lower esophageal sphincter relaxation pharmacokinetic-pharmacodynamic modeling: count model and repeated time-to-event model. J Pharmacol Exp Ther. 2011;339(3):878–85.

    Article  CAS  PubMed  Google Scholar 

  27. Karlsson MO, Schoemaker RC, Kemp B, Cohen AF, van Gerven JM, Tuk B, et al. A pharmacodynamic Markov mixed-effects model for the effect of temazepam on sleep. Clin Pharmacol Ther. 2000;68(2):175–88.

  28. Lacroix BD, Karlsson MO, Friberg LE. Simultaneous exposure-response modeling of ACR20, ACR50, and ACR70 improvement scores in rheumatoid arthritis patients treated with Certolizumab Pegol. CPT Pharmacometrics Syst Pharmacol. 2014;3:e143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pinana JL, Perez-Pitarch A, Guglieri-Lopez B, Gimenez E, Hernandez-Boluda JC, Terol MJ, et al. Sirolimus exposure and the occurrence of cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation. Am J Transplant. 2018;18(12):2885–94.

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Authors and Affiliations

  1. Division of Neuropsychiatric Pharmacology, Office of Clinical Pharmacology, US Food and Drug Administration, 10903 New Hampshire Avenue, White Oak Building 51, RM 2116, Silver Spring, MD, 20993, USA

    Alejandro Perez-Pitarch, Gopichand Gottipati, Ramana Uppoor, Mehul Mehta & Sreedharan Sabarinath

Authors
  1. Alejandro Perez-Pitarch
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  2. Gopichand Gottipati
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  3. Ramana Uppoor
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  4. Mehul Mehta
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  5. Sreedharan Sabarinath
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Correspondence to Sreedharan Sabarinath.

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Perez-Pitarch, A., Gottipati, G., Uppoor, R. et al. An Innovative Pharmacometric Approach for the Simultaneous Analysis of Frequency, Duration and Severity of Migraine Events. Pharm Res 37, 189 (2020). https://doi.org/10.1007/s11095-020-02907-8

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  • DOI: https://doi.org/10.1007/s11095-020-02907-8

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