Mark Whitlock, Laura Iavarone
Pfizer Pharmaceuticals
Objectives: Headache is a common adverse event in clinical studies [1]. The objective of this analysis was to examine the effect of systemic exposure to drug X on the incidence of headaches with the final aim of proposing a better tolerated dosing regimen for future trials with this drug.
Methods: The overall analysis consists of two sections: (1) a population PK model to estimate individual exposure, (2) a PK/PD model to correlate individual exposure to severity and duration of headache. For the development of the PK model a dataset of 168 subjects (from either single and repeat dose studies) was used. For the implementation of the PK/PD model of headache the subset of data coming from the repeat dose studies only have been considered.
Two and three compartment models with first-order and zero order absorption were evaluated. The effect of covariates such as dose, fed/fasted conditions, formulation (either suspension or tablet) and body weight have been assessed.Individual PK parameter (Cmax, AUCt, cumulative Cmax and cumulative AUCt) values have been estimated for the inclusion in the PK/PD model.
The probability of getting a moderate headache was modelled using a mixed effects ordinal logistic regression model with concentration and time as covariates and subject as a random effect.
Results: The disposition kinetics were best modelled with 2 compartments with first order absorption rate constant (ka) and a lag-time parameter (Tlag) to characterize the absorption process. Allometric factors on CL/F and Vc were included in the final model. Different ka have been estimated for suspension and tablet and, within suspension, different ka's have been estimated for dose below and above 600mg. There was a statistically significant relationship between the severity of headache and both concentration and the rate of exposure. It was shown that the probability of a moderate headache increased with concentration but was reduced when concentrations were increased at a slower rate.
Conclusions: The innovative modelling of the relationship between the headache and pK data has provided an understanding of how to improve tolerability through use of titration.
References:
[1] Anna Ferrari et al. J Headache Pain (2009) 10:235-239 Focus on headache as an adverse reaction to drugs
Reference: PAGE 21 (2012) Abstr 2410 [www.page-meeting.org/?abstract=2410]
Poster: Safety (e.g. QT prolongation)