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

Abstract

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...

At Physiologically Relevant Concentrations, Valproic Acid and Lithium Carbonate Reduce Oxidative Stress in Human Astrocytoma Cells

“…26,27 Unlike lithium, VPA binds well to plasma proteins (>90%), particularly albumin. 26,28 This binding is saturable, with free VPA fraction higher when total plasma concentrations are elevated. 28 The unbound portion is considered pharmacologically-active and able to cross the BBB, with reports of brain to serum ratios varying from 0.068-0.540 after VPA administration.…”

“…26,28 This binding is saturable, with free VPA fraction higher when total plasma concentrations are elevated. 28 The unbound portion is considered pharmacologically-active and able to cross the BBB, with reports of brain to serum ratios varying from 0.068-0.540 after VPA administration. [29][30][31][32] As such, it is estimated that, at therapeutic doses, brain concentration sit between 20-325 μM; however, available in vitro studies have not actively addressed this: Tan et al 33 used 1 mM VPA in primary rat cortical cells; Wang et al 34 used primary rat astrocyte cells and 0.3-1.2 mM VPA; and Zhang et al 35 used human glioblastoma U87 cell line and 2-16 mM VPA.…”