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Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis

Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of t...

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Autores principales: Nakashima, Hiroo, Oniki, Kentaro, Nishimura, Miki, Ogusu, Naoki, Shimomasuda, Masatsugu, Ono, Tatsumasa, Matsuda, Kazuki, Yasui-Furukori, Norio, Nakagawa, Kazuko, Ishitsu, Takateru, Saruwatari, Junji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617862/
https://www.ncbi.nlm.nih.gov/pubmed/26484865
http://dx.doi.org/10.1371/journal.pone.0141266
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author Nakashima, Hiroo
Oniki, Kentaro
Nishimura, Miki
Ogusu, Naoki
Shimomasuda, Masatsugu
Ono, Tatsumasa
Matsuda, Kazuki
Yasui-Furukori, Norio
Nakagawa, Kazuko
Ishitsu, Takateru
Saruwatari, Junji
author_facet Nakashima, Hiroo
Oniki, Kentaro
Nishimura, Miki
Ogusu, Naoki
Shimomasuda, Masatsugu
Ono, Tatsumasa
Matsuda, Kazuki
Yasui-Furukori, Norio
Nakagawa, Kazuko
Ishitsu, Takateru
Saruwatari, Junji
author_sort Nakashima, Hiroo
collection PubMed
description Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient. This retrospective study included 77 VPA-treated Japanese patients with epilepsy. A nonlinear mixed-effects model best represented the relationship between the trough concentrations of VPA at steady-state and an over 50% reduction in seizure frequency. The model was fitted using a logistic regression model, in which the logit function of the probability was a linear function of the predicted trough concentration of VPA. The model showed that the age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and co-administration of carbamazepine, clonazepam, phenytoin or topiramate were associated with an over 50% reduction in the seizure frequency. We plotted the receiver operating characteristic (ROC) curve for the logit(Pr) value of the model and the presence or absence of a more than 50% reduction in seizure frequency, and the areas under the curves with the 95% confidence interval from the ROC curve were 0.823 with 0.793–0.853. A logit(Pr) value of 0.1 was considered the optimal cut-off point (sensitivity = 71.8% and specificity = 80.4%), and we calculated the optimal trough concentration of VPA for each patient. Such parameters may be useful to determine the recommended therapeutic concentration of VPA for each patient, and the procedure may contribute to the further development of personalized pharmacological therapy for epilepsy.
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spelling pubmed-46178622015-10-29 Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis Nakashima, Hiroo Oniki, Kentaro Nishimura, Miki Ogusu, Naoki Shimomasuda, Masatsugu Ono, Tatsumasa Matsuda, Kazuki Yasui-Furukori, Norio Nakagawa, Kazuko Ishitsu, Takateru Saruwatari, Junji PLoS One Research Article Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient. This retrospective study included 77 VPA-treated Japanese patients with epilepsy. A nonlinear mixed-effects model best represented the relationship between the trough concentrations of VPA at steady-state and an over 50% reduction in seizure frequency. The model was fitted using a logistic regression model, in which the logit function of the probability was a linear function of the predicted trough concentration of VPA. The model showed that the age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and co-administration of carbamazepine, clonazepam, phenytoin or topiramate were associated with an over 50% reduction in the seizure frequency. We plotted the receiver operating characteristic (ROC) curve for the logit(Pr) value of the model and the presence or absence of a more than 50% reduction in seizure frequency, and the areas under the curves with the 95% confidence interval from the ROC curve were 0.823 with 0.793–0.853. A logit(Pr) value of 0.1 was considered the optimal cut-off point (sensitivity = 71.8% and specificity = 80.4%), and we calculated the optimal trough concentration of VPA for each patient. Such parameters may be useful to determine the recommended therapeutic concentration of VPA for each patient, and the procedure may contribute to the further development of personalized pharmacological therapy for epilepsy. Public Library of Science 2015-10-20 /pmc/articles/PMC4617862/ /pubmed/26484865 http://dx.doi.org/10.1371/journal.pone.0141266 Text en © 2015 Nakashima et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Nakashima, Hiroo
Oniki, Kentaro
Nishimura, Miki
Ogusu, Naoki
Shimomasuda, Masatsugu
Ono, Tatsumasa
Matsuda, Kazuki
Yasui-Furukori, Norio
Nakagawa, Kazuko
Ishitsu, Takateru
Saruwatari, Junji
Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis
title Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis
title_full Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis
title_fullStr Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis
title_full_unstemmed Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis
title_short Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis
title_sort determination of the optimal concentration of valproic acid in patients with epilepsy: a population pharmacokinetic-pharmacodynamic analysis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617862/
https://www.ncbi.nlm.nih.gov/pubmed/26484865
http://dx.doi.org/10.1371/journal.pone.0141266
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