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



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


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.


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.


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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Repeated time-to-categorical event


Visual predictive check


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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).

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Key Words

  • Time-to-event
  • ordered categorical
  • Markov model
  • migraine prevention