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Analysis of exposure-response of CI-945 in patients with epilepsy: application of novel mixed hidden Markov modeling methodology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
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2012 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 39, no 3, 263-271 p.Article in journal (Refereed) Published
Abstract [en]

We propose to describe exposure-response relationship of an antiepileptic agent, using mixed hidden Markov modeling methodology, to reveal additional insights in the mode of the drug action which the novel approach offers. Daily seizure frequency data from six clinical studies including patients who received gabapentin were available for the analysis. In the model, seizure frequencies are governed by underlying unobserved disease activity states. Individual neighbouring states are dependent, like in reality and they exhibit their own dynamics with patients transitioning between low and high disease states, according to a set of transition probabilities. Our methodology enables estimation of unobserved disease dynamics and daily seizure frequencies in all disease states. Additional modes of drug action are achievable: gabapentin may influence both daily seizure frequencies and disease state dynamics. Gabapentin significantly reduced seizure frequencies in both disease activity states; however it did not significatively affect disease dynamics. Mixed hidden Markov modeling is able to mimic dynamics of seizure frequencies very well. It offers novel insights into understanding disease dynamics in epilepsy and gabapentin mode of action.

Place, publisher, year, edition, pages
2012. Vol. 39, no 3, 263-271 p.
Keyword [en]
Mixed hidden Markov model, Epilepsy, CI-945, Maximum likelihood estimation, Monolix
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-176817DOI: 10.1007/s10928-012-9248-2ISI: 000304617500004OAI: oai:DiVA.org:uu-176817DiVA: diva2:537725
Available from: 2012-06-27 Created: 2012-06-26 Last updated: 2012-06-27Bibliographically approved

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Karlsson, Mats O.
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