Hugo Maas, Meindert Danhof, Oscar Della Pasqua
LACDR, Leiden University, Division of Pharmacology
Triptans (such as sumatriptan and naratriptan) are efficacious and specific medications in the treatment of migraine. Yet, assessing clear pharmacokinetic-pharmacodynamic (PK-PD) relations for these drugs is difficult. In most clinical studies the actions of triptans in the trigeminal system are measured indirectly using pain-rating scales. As a consequence , sources of variability originating from the multiple levels of pain control are added to the original trigeminal signal. Furthermore, little is known about the kinetics of pathophysiological mechanisms involved in migraine, which complicates the design of predictive mechanism-based models.
In principle a PK-PD model for triptans should be based on a set of physiologically meaningful parameters. The facts that little information on the disease is available and that the endpoint is a categorical variable, impose that the model be stochastic. A class of structural models that provide these features are the hidden Markov models.
To test the hidden Markov model concept, a model was developed to describe the course of a single migraine attack treated with either sumatriptan or naratriptan. It consists of two layers: i) a hidden layer representing the (unobserved) states of trigeminal activity and ii) an observational layer that transforms trigeminal activity into a headache score. The parameters in the first layer of the model include the elements of the intensity matrix, which can be considered rate constants of the trigeminal activation process. Triptan plasma concentrations act as covariates increasing the forward transition rates. The headache scores returned by the observational layer are multinomially distributed conditional on the unobserved state. The parameters in this layer are the elements of the emission matrix, reflecting the influence of pain control processes on the trigeminal pain signal.
The model estimates disease-related parameters (transition rates and score probabilities) and drug-related parameters (EC50 and Emax). In this study, parameter estimates obtained from analysis of sumatriptan data are compared with those obtained from analysis of naratriptan data.
Reference: PAGE 13 (2004) Abstr 494 [www.page-meeting.org/?abstract=494]
Poster: poster