Pharmacokinetic Parameters of Total and Unbound Valproic Acid and Their Relationships to Seizure Control in Epileptic Children

Ayudhya, Duangchit Panomvana Na; Suwanmanee, Jintana; Visudtibhan, Anainnit

doi:10.1097/01.mjt.0000155113.89092.58

Cited by 15 publications

(4 citation statements)

References 8 publications

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“…In addition, Panomvana Na Ayudhya et al reported that seizure uncontrolled paediatric patients had a significantly higher elimination rate constant (K e ) and a significantly shorter half-life of VPA. However, the sample size of this study was relatively small and future study with a larger sample size is required to confirm the results [51]. With regard to psychiatric patients, even though a therapeutic range for mood-stabilizing activity of VPA has not yet been published, several studies reported that a concentration of at least 50 mg l À1 might be required to achieve clinical response in WT, BMI, age, gender, co-medication (PNZ, THP, CZP, RPD, HPD, CPZ), VPA dose…”

Section: Discussionmentioning

confidence: 76%

A systematic review of population pharmacokinetics of valproic acid

Methaneethorn

2018

Brit J Clinical Pharma

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Keywords nonlinear mixed effect modelling, population pharmacokinetics, systematic review, valproic acid AIMSPopulation pharmacokinetics is an essential tool that helps guide individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of valproic acid (VPA) and to identify factors influencing VPA pharmacokinetic variability. METHODSPubMed and Embase databases were systematically searched from inception to June, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of VPA conducted in humans and that employed a nonlinear mixed effect modelling approach were included in this review. RESULTSTwenty-six studies were included in this review. Most studies characterized VPA pharmacokinetics as a one-compartment model. Three studies reported a two-compartment model. Body weight, dose and age were significant predictors for VPA volume of distribution (V d ). The estimated V d for one-compartment models ranged from 8.4 to 23.3 l. For two-compartment models, peripheral volumes of distribution ranged from 4.08 to 42.1 l. Frequently reported significant predictors for VPA clearance (CL VPA ) included body weight, VPA dose, concomitant medications, gender and age. The estimated CL VPA ranged from 0.206 to 1.154 l h À1 and the inter-individual variability ranged from 13.40 to 35.90%. Two studies reported population pharmacokinetics/pharmacodynamics of VPA in patients with epilepsy. Seventeen studies evaluated the performance of their final models. CONCLUSIONSSignificant predictors influencing VPA pharmacokinetics as well as model methodologies are highlighted in this review. For clinical application, CL VPA could be predicted using body weight, VPA dose, concomitant medications, gender or age. For future research, there is a knowledge gap regarding population pharmacokinetics/pharmacodynamics of VPA in a population other than epileptic patients.British Journal of Clinical Pharmacology Br J Clin Pharmacol (2018) 84 816-834 816

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Section: Discussionmentioning

confidence: 76%

A systematic review of population pharmacokinetics of valproic acid

Methaneethorn

2018

Brit J Clinical Pharma

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“…Valproate (VPA) is a short-chain fatty acid with HDAC inhibitor activity that is widely prescribed as one of the first-line medications for epilepsy and bipolar disorders [10], [11], [12], [13]. Chronic VPA treatment in bipolar patients often restricts the frequency of mood swings to either the manic or depressive state [14].…”

Section: Introductionmentioning

confidence: 99%

Valproate Alters Dopamine Signaling in Association with Induction of Par-4 Protein Expression

et al. 2012

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Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism.

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“…Both the elimination rate constant and volume of distribution of the unbound VPA are much higher than those of the total VPA; clearance was approximately 10-fold higher. The amount of VPA not bound to proteins is linearly dependent on the dose administered [83].…”

Section: Hdaci Pharmacokinetics Short Chain Fatty Acidsmentioning

confidence: 99%

Histone Deacetylase Inhibitors: Molecular and Biological Activity as a Premise to Clinical Application

Santini¹,

Gozzini²,

Ferrari

2007

CDM

126

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Epigenetic modifications are reversible chromatin rearrangements that in normal cells modulate gene expression, without changing DNA sequence. Alterations of this equilibrium, mainly affecting the two interdependent mechanisms of DNA methylation and histone acetylation, are frequently involved in the genesis of cancer. The histone code, regulating gene expression, is constituted by the combination of different acetylated lysine residues of histones. In neoplastic cells, the abundance of deacetylated histones is usually associated with DNA hypermethylation and gene silencing. Several compounds, known to have in vitro antineoplastic activity, have been eventually shown to act as histone deacetylase inhibitors. Thus, HDAC inhibitors have been successfully introduced in clinical trials as antitumour agents. They are classified according to their chemical structures and are endowed with different specificity and affinity for the HDACs of classes 1, 2, 4. Among HDAC inhibitors, the most potent are the hydroxamic acid derivatives, like SAHA, which has been recently approved for therapy of cutaneous T-cell lymphomas. Other classes of HDAC inhibitors are short chain fatty acids (SCFA), benzamides, epoxyketone and non-epoxyketone containing cyclic tetrapeptides, and hybrid molecules. SCFA, although widely used (especially valproic acid) and clinically efficacious, have weak HDAC inhibition constants. Benzamides, like MS-275, and cyclic peptides, like depsipeptide, have been studied in numerous clinical trials and demonstrated low toxicity and activity in solid and haematological neoplasms. HDAC inhibitors are also potent radiation sensitizers. Their future in oncology may thus be based on their activity as single agents and on their synergy with the hypomethylating drugs and with chemo- and radiotherapeutics.

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Pharmacokinetic Parameters of Total and Unbound Valproic Acid and Their Relationships to Seizure Control in Epileptic Children

Cited by 15 publications

References 8 publications

A systematic review of population pharmacokinetics of valproic acid

A systematic review of population pharmacokinetics of valproic acid

Valproate Alters Dopamine Signaling in Association with Induction of Par-4 Protein Expression

Histone Deacetylase Inhibitors: Molecular and Biological Activity as a Premise to Clinical Application

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