title: Analysis of exposure-response of CI-945 in patients with epilepsy: application of novel mixed hidden Markov modeling methodology.
abstract: 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.
authors.affiliation: INRIA Saclay Île de France & Département de Mathématiques, Faculté des Sciences d'Orsay, Université Paris-Sud 11, 91405 Orsay Cedex, France. maud.delattre@math.u-psud.fr
authors.forename: Maud
authors.initials: M
authors.lastname: Delattre
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.forename: Raymond
authors.initials: R
authors.lastname: Miller
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Marc
authors.initials: M
authors.lastname: Lavielle
mesh_terms: D000293:Adolescent; D000328:Adult; D000588:Amines / Q000627:therapeutic use*; D000927:Anticonvulsants / Q000627:therapeutic use*; D002648:Child; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004827:Epilepsy / Q000188:drug therapy* / Q000453:epidemiology*; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin