Determinants of free serum valproate concentration: A prospective study in patients on divalproex sodium monotherapy

Nasreddine, Wassim; Dirani, Maya; Atweh, Samir; Makki, Achraf; Beydoun, Ahmad

doi:10.1016/j.seizure.2018.04.012

Cited by 31 publications

(25 citation statements)

References 21 publications

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“…Although several studies have demonstrated that free serum concentration has a stronger association with adverse effects than does total serum concentration, total serum concentration is adopted more widely for technical and economic reasons [ 4 , 17 ]. However, free and total VPA serum concentrations are highly discordant because of the unpredictable free fraction, particularly in case of higher total VPA serum concentration (>60 mcg/mL) and hypoalbuminemia [ 4 , 8 , 9 ]. Riker et al [ 10 ] analyzed VPA use in 15 patients in an intensive care unit and reported a considerable variation in free fraction, ranging from 15% to 89%.…”

Section: Discussionmentioning

confidence: 99%

“…Free VPA is responsible for the drug's pharmacologic effects but also for its toxicity. At a normal albumin concentration and low total serum concentration (20-60 mcg/mL), the unbound fraction of VPA is approximately 10% of the total serum concentration [8]. The unbound fraction might exceed 15% when total serum concentration is higher than 100 mcg/mL [8].…”

Section: Introductionmentioning

confidence: 99%

“…At a normal albumin concentration and low total serum concentration (20-60 mcg/mL), the unbound fraction of VPA is approximately 10% of the total serum concentration [8]. The unbound fraction might exceed 15% when total serum concentration is higher than 100 mcg/mL [8]. In addition to high VPA serum concentration, hypoalbuminemia is another critical factor that increases the unbound fraction of VPA, potentially increasing toxicity, particularly for inpatients [4].…”

Section: Introductionmentioning

confidence: 99%

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Safety range of free valproic acid serum concentration in adult patients

et al. 2020

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Background Therapeutic drug monitoring (TDM) is recommended during valproic acid (VPA) use, and total serum concentration has been widely adopted. However, the free form of VPA is responsible for its pharmacologic and toxic effects, and the total and free concentrations are highly discordant because of VPA's highly protein bound and saturable binding characteristics. Therefore, free VPA monitoring is increasingly advocated. Nevertheless, the correlation between free VPA concentration and associated adverse effects remains unknown. Objective To determine the optimal safety range of free VPA concentration in adult patients. Materials and methods This prospective cohort study enrolled adult patients undergoing VPA therapy with TDM. Patient characteristics, VPA use, and adverse effects (thrombocytopenia, hyperammonemia, and hepatotoxicity) were recorded. A multivariate logistic regression model was applied to identify the predictors of adverse effects, and the receiver operating characteristic curve was applied to locate the cutoff point of free VPA concentration. Results A total of 98 free serum concentrations from 51 patients were included for final analysis. In total, 31 (31.6%), 27 (27.6%), and 4 (4.1%) episodes of hyperammonemia, thrombocytopenia, and hepatotoxicity were observed, respectively. Free VPA concentration was a predicting factor for thrombocytopenia but not for hyperammonemia. A free VPA concentration of >14.67 mcg/mL had the greatest discriminating power (area under the curve = 0.77) for the occurrence of thrombocytopenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Safety range of free valproic acid serum concentration in adult patients

et al. 2020

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“…Thus, free fractions of unbound compound (e.g. VPA ~0.3 -0.5 mM, phenytoin ~3 -9 µM) reflect human therapeutic concentrations more appropriately, when they are set into correlation with free in vitro concentrations of the human gastruloid model, since the E6 human gastruloid medium is free of serum albumin [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

In vitroteratogenicity testing using a 3D, embryo-like gastruloid system

Mantziou

Baillie-Benson

Jaklin

et al. 2021

Preprint

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Pharmaceuticals that are intended for use in patients of childbearing potential need to be tested for teratogenicity before marketing. Several pharmaceutical companies use animal-free in vitro models which allow a more rapid selection of lead compounds and contribute to 3Rs principles (‘replace, reduce and refine’) by streamlining the selection of promising compounds that are submitted to further regulatory studies in animals. Currently available in vitro models typically rely on adherent monolayer cultures or disorganized 3D structures, both of which lack the spatiotemporal and morphological context of the developing embryo. A newly developed 3D 'gastruloid' model has the potential to achieve a more reliable prediction of teratogenicity by providing a robust recapitulation of gastrulation-like events alongside morphological coordination at relatively high-throughput. In this first proof-of-concept study, we used both mouse and human gastruloids to examine a panel of seven reference compounds, with associated in vivo data and known teratogenic risk, to quantitatively assess in vitro teratogenicity. We observed several gross morphological effects, including significantly reduced elongation or decreased size of the gastruloids, upon exposure to several of the reference compounds. We also observed aberrant gene expression using fluorescent reporters, including SOX2, BRA, and SOX17, suggestive of multi-lineage differentiation defects and disrupted axial patterning. Finally, we saw that gastruloids recapitulated some of the known in vivo species-specific susceptibilities between their mouse and human counterparts. We therefore suggest that gastruloids represent a powerful tool for teratogenicity assessment by enabling relevant physiological recapitulation of early embryonic development, demonstrating their use as a novel in vitro teratogenic model system.

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“…A Japanese study 42 found a total VPA concentration of 71.2 ± 32.3 µg/mL in epilepsy patients, with a free concentration of 7.05 ± 5.84 µg/mL and a plasma protein binding rate of 90.1%. Wassim et al 35 reported a VPA protein binding rate of around 83.0% in 902 Arabians (10-75 years old), while the average free drug concentration was 18.3 µg/mL. Drisaldi et al 43 investigated 174 American adults and determined a free VPA concentration range of 7-23 µg/mL; the free VPA concentration range in an intensive care unit (ICU) of Miami was 5-17 µg/mL, while plasma protein binding levels were 48% on average.…”

Section: Associations Of Vpa Free Concentration With Total Concentration and Plasma Protein Binding Ratementioning

confidence: 99%

CYP2C93/3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy

Dong

et al. 2021

PGPM

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Purpose To perform therapeutic drug monitoring (TDM) of total and free plasma valproic acid (VPA) concentrations in pediatric patients with epilepsy and to analyze related factors. Patients and Methods Pediatric epileptic patients treated in 2015–2019 in our hospital were assessed. Total and free plasma VPA concentrations were obtained by UPLC and LC-MS/MS, respectively. Regression analysis was performed to examine the associations of free plasma VPA with total plasma VPA and plasma protein binding rate. The impacts of individual situation, CYP2C9 genotype, and drug combination on VPA concentration were examined. Results Of the 251 patients, 81 had lower total concentrations than effective therapeutic levels; 86 and 31 patients had infections and central nervous system dysplasia, respectively. VPA’s daily doses and free drug concentrations were significantly lower in the CYP2C9 *3/*3 genotype group versus the CYP2C9 *1/*3 and CYP2C9 *1/*1 groups ( P <0.05). Free and total VPA concentrations were linked by Y = 0.0004 X 2 + 0.042 X + 0.3035 (r=0.6981); VPA plasma protein binding rate and free VPA concentration were related by Y = 0.0003 X 2 - 0.0127 X + 0.9777 (r=0.8136). Both total and free VPA concentrations were significantly decreased in patients simultaneously administered phenobarbital, meropenem and biapenem ( P <0.05), with therapeutic failure after meropenem/biapenem co-administration. Conclusion Free VPA amounts have nonlinear relationships with total VPA amounts and plasma protein binding rate in epileptic children. Additionally, CYP2C9 *3/*3 expression affects VPA metabolism. Since phenobarbital affects VPA metabolism, TDM is recommended. Meanwhile, carbapenem-co-administration with VPA should be prohibited.

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Determinants of free serum valproate concentration: A prospective study in patients on divalproex sodium monotherapy

Cited by 31 publications

References 21 publications

Safety range of free valproic acid serum concentration in adult patients

Safety range of free valproic acid serum concentration in adult patients

In vitroteratogenicity testing using a 3D, embryo-like gastruloid system

CYP2C93/3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy

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Determinants of free serum valproate concentration: A prospective study in patients on divalproex sodium monotherapy

Cited by 31 publications

References 21 publications

Safety range of free valproic acid serum concentration in adult patients

Safety range of free valproic acid serum concentration in adult patients

In vitroteratogenicity testing using a 3D, embryo-like gastruloid system

CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy

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CYP2C93/3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy