An Innovative Pharmacometric Approach for the Simultaneous Analysis of Frequency, Duration and Severity of Migraine Even
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RESEARCH PAPER
An Innovative Pharmacometric Approach for the Simultaneous Analysis of Frequency, Duration and Severity of Migraine Events Alejandro Perez-Pitarch 1 & Gopichand Gottipati 1 & Ramana Uppoor 1 & Mehul Mehta 1 & Sreedharan Sabarinath 1
Received: 20 May 2020 / Accepted: 10 August 2020 # This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2020
ABSTRACT Purpose To explore the use of a multistate repeated, time-tocategorical 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 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02907-8) contains supplementary material, which is available to authorized users. * Sreedharan Sabarinath [email protected] 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
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.
KEY WORDS Time-to-event . ordered categorical . Markov model . migraine prevention . NONMEM
ABBREVIATIONS RTTCE VPC
Repeated time-to-categorical event Visual predictive check
INTRODUCTION Migraine was ranked as the seventh leading cause overall, and fifth leading cause in adolescents and young adults (aged between 15 and 39 years) for the number of years lived in disability globally in 2015 (1). Despite being underdiagnosed, it is known to affect roughly a billion people globally and within the United States alone, the projected migraine-related health burden is estimated to be over US $ 11 bill
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