Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children

Ueshima, Satoshi; Aiba, Tetsuya; Makita, Tetsuji; Nishihara, Shuichiro; Kitamura, Yoshihisa; Kurosaki, Yuji; Kawasaki, Hiromu; Sendo, Toshiaki; Ohtsuka, Yoko; Gomita, Yutaka

doi:10.1111/j.1365-2710.2008.00885.x

Cited by 21 publications

(21 citation statements)

References 27 publications

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“…Several other groups (Imai et al 2003;Roh et al 2004;Watanabe et al 2005) have reported growth inhibition and sensitization to Fas-mediated cell death of human osteosarcoma cells by HDAC inhibitors, FR901228 and TSA, but not inhibition of soluble Fas secretion. Importantly, our results showed that VPA exerted its eVects at concentrations which are attainable in sera of patients administered with VPA orally without serious side eVects (Johannessen and Johannessen 2003;Chavez-Blanco et al 2005;Allen et al 2006;Ueshima et al 2008). These results indicate the possibility that VPA may be applicable to the treatment of osteosarcomas.…”

Section: Discussionmentioning

confidence: 54%

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

Yamanegi

Yamane

Hara

et al. 2008

J Cancer Res Clin Oncol

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Section: Discussionmentioning

confidence: 54%

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

Yamanegi

Yamane

Hara

et al. 2008

J Cancer Res Clin Oncol

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“…In fact, there have been several studies on the estimation and/or a regression equation to predict the unbound from the total concentration. [9][10][11] However, as revealed in our previous study, the equation for epileptic children or adult patients is not applicable for epileptic infants aged less than 1 year old. The unbound serum VPA concentrations in infants vary patient by patient more markedly than those in children, and, thereby, their total and unbound VPA concentrations are poorly correlated (Fig.…”

mentioning

confidence: 93%

“…2). Lastly, the predicted value calculated with Model 85 was compared with the value calculated using the previously reported equation, 11) indicating that the prediction improves and the variability of the prediction is smaller when the calculation is performed with Model 85 (Fig. 3).…”

Section: Characterization Of the Serum Unbound Vpa Concentration Profmentioning

confidence: 99%

“…17) In this analysis, the Langmuir equation was used to characterize the relationship. 11,18) That is, the relationship between the total (Ct) and unbound (Cf ) serum VPA concentrations in the jth record of the ith infant is described as follows, taking into account intra-individual variability, e: (3) where Bm i designates the maximum concentration of the VPA binding site on the serum protein in the ith infant, and Kd i designates the dissociation constant between the serum protein and VPA in the ith infant. Then, these parameters are described with population mean parameters (q) as follows: (4) where q 1 and q 2 are the parameters to be determined in this study.…”

Section: Data Source For Analysismentioning

confidence: 99%

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Empirical Approach for Improved Estimation of Unbound Serum Concentrations of Valproic Acid in Epileptic Infants by Considering Their Physical Development

Ueshima

Aiba

Sato

et al. 2011

Biological & Pharmaceutical Bulletin

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Valproic acid (VPA) is known to have a broad antiepileptic spectrum for partial and generalized seizures, and it has also been shown to be effective for intractable epilepsy when used at a higher dose than that generally recommended.1,2) With these properties, it is one of the widely prescribed compounds for epilepsy, but it should be noted that an excess increase in the serum VPA concentration inevitably elevates the risk of adverse reactions, such as hepatic dysfunction, 3) thrombocytopenia, 4) and hyperammonemic encephalopathy. 5)Since it has been considered that the unbound serum VPA concentration is closely related to the antiepileptic action of VPA and its adverse effects, 6) determination of the unbound VPA concentration via therapeutic drug monitoring (TDM) is essential to optimize the therapeutic efficacy of VPA. 7,8) However, the total serum VPA concentration is commonly analyzed instead of its unbound concentration in TDM activities, due to the cost-ineffective and time-consuming procedures necessary for measuring the unbound concentration.One approach to evaluate the unbound serum VPA concentration without performing such procedures is to estimate it based on its total serum concentration. In fact, there have been several studies on the estimation and/or a regression equation to predict the unbound from the total concentration.9-11) However, as revealed in our previous study, the equation for epileptic children or adult patients is not applicable for epileptic infants aged less than 1 year old. The unbound serum VPA concentrations in infants vary patient by patient more markedly than those in children, and, thereby, their total and unbound VPA concentrations are poorly correlated (Fig. 1). 12) This means that the unbound VPA concentration in an epileptic infant needs to be directly measured through TDM activities, but he/she is usually so small that it is difficult to draw a volume of blood large enough for measurement. In conjunction with the fact that the adverse reactions of VPA frequently occur in infants, 13,14) it is therefore important to develop an equation to properly estimate the unbound VPA concentration for epileptic infants.To devise such an equation, we chose an empirical approach involving compensating for the equation in children by identifying a factor affecting the unbound VPA concentration. In addition, the parameter to be used for the compensation should be noninvasive, or some measurable value that can be determined without blood drawing. In this study, we The unbound serum concentration of valproic acid (VPA) is closely related to its therapeutic efficacy. In epileptic infants, the unbound VPA concentration varies largely from patient to patient, being difficult to predict using the reported equations for older children. To establish an equation to estimate the unbound concentration in infants, we empirically characterized the relationship between total and unbound VPA concentrations, taking their growth and development into consideration. Data were retrospectively collected fro...

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“…Some authors have focused therefore on the free concentrations or free fraction of AEDs (e.g. carbamazepine [26], phenytoin [27], and valproate [28]). In these publications, the free plasma concentration of the drug was found to better reflect the concentrations of the extracellular space (ECS) and the brain's interstitial fluid.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Dijkman

Álvarez-Jiménez

Danhof

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.

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Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children

Cited by 21 publications

References 27 publications

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

Empirical Approach for Improved Estimation of Unbound Serum Concentrations of Valproic Acid in Epileptic Infants by Considering Their Physical Development

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

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