Population pharmacokinetics of unbound valproic acid in pediatric epilepsy patients in China: a protein binding model

Gu, Xurui; Zhu, Min; Sheng, Changcheng; Yu, Shuran; Peng, Qilin; Ma, Mubai; Hu, Yani; Li, Ziran; Jiao, Zheng; Zhou, Boting

doi:10.1007/s00228-020-03080-y

Cited by 15 publications

(25 citation statements)

References 32 publications

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“…Among the known polymorphic sites of CYP2C9 gene, the CYP2C9*3 mutation is commonly detected in the Chinese population, while the mutation of CYP2C9*2 is rarely reported [ 44 ]. Studies have shown that the metabolites of VPA include 4-Ene-VPA, 4-OH-VPA, and 5-OH-VPA, with 4-Ene-VPA confirmed to show liver toxicity [ 45 ]. In the CYP2C9 heterozygous mutant, the production of 4-Ene-VPA is 29% less than that of the wild homozygotes, while the mutant homozygotes generate 61% less of 4-Ene-VPA compared to wild homozygotes, indicating that patients with wild-type CYP2C9*1 are more likely to show liver toxicity than the carriers of CYP2C9*3 .…”

Section: Valproic Acidmentioning

confidence: 99%

“…These studies conclude that both CYP2C9 and CYP2C19 are involved in the metabolism of VPA in humans with their genetic polymorphisms significantly affecting the metabolic process of VPA [ 45–50 ]. Therefore, in clinical treatments, it is substantially important to detect the genotype of patients in order to establish precise formulation of individualized drug dosages and to effectively avoid drug waste and adverse reactions, exhibiting significant clinical importance for individualized drug application.…”

Section: Valproic Acidmentioning

confidence: 99%

“…Symbol ‘ – ’ indicates information not available. Symbols ‘↑’ and ‘↓’ indicate the increase and decrease of the drug plasma concentration, respectively AED Genetic polymorphism Gene Locus Allele Effect on the plasma concentration or other effects Reference Clinical recommendation on dosage Valproic acid CYP450 CYP2A6 CYP2A6*4 CYP2A6*4 ↑ [ 31 ] Decrease CYP2B6 c.516 G > T; c.785A>G CYP2B6*6 ↑ [ 39 ] Decrease CYP2C9 c.1075A>C CYP2C9*3 Low probability of liver toxicity [ 45 ] Decrease CYP2C19 c.681 G > A CYP2C19*2 ↑ [ 46 ] Decrease c.636 G > A CYP2C19*3 ↑ [ 46 ] Decrease CYP2D6 c.100C>T CYP2D6*10 – [ 54 ] – UGT UGT1A3 c.31 T > C UGT1A3*2 ↓ [ 61 ] Increase …”

Section: Summary and Prospectmentioning

confidence: 99%

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Effects of genetic polymorphism of drug-metabolizing enzymes on the plasma concentrations of antiepileptic drugs in Chinese population

Zhao

Meng

2022

Bioengineered

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As a chronic brain disease, epilepsy affects ~50 million people worldwide. The traditional antiepileptic drugs (AEDs) are widely applied but showing various problems. Although the new AEDs have partially solved the problems of traditional AEDs, the current clinical application of traditional AEDs are not completely replaced by new drugs, particularly due to the large individual differences in drug plasma concentrations and narrow therapeutic windows among patients. Therefore, it is still clinically important to continue to treat patients using traditional AEDs with individualized therapeutic plans. To date, our understanding of the molecular and genetic mechanisms regulating plasma concentrations of AEDs has advanced rapidly, expanding the knowledge on the effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of AEDs. It is increasingly imperative to summarize and conceptualize the clinical significance of recent studies on individualized therapeutic regimens. In this review, we extensively summarize the critical effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of several commonly used AEDs as well as the clinical significance of testing genotypes related to drug metabolism on individualized drug dosage. Our review provides solid experimental evidence and clinical guidance for the therapeutic applications of these AEDs.

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Section: Valproic Acidmentioning

confidence: 99%

Section: Valproic Acidmentioning

confidence: 99%

Section: Summary and Prospectmentioning

confidence: 99%

See 1 more Smart Citation

Effects of genetic polymorphism of drug-metabolizing enzymes on the plasma concentrations of antiepileptic drugs in Chinese population

Zhao

Meng

2022

Bioengineered

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“…Also, some adverse drug reactions have been reported including gastrointestinal symptoms, sedation, increased appetite with weight gain, hair loss, tremor, and ataxia ( Methaneethorn, 2018 ; Guo et al, 2019 ). In addition, approximately only 5–10% of VPA is free in the plasma, and the association between VPA dose and systemic exposure level is curvilinear ( Gu et al, 2021 ). Moreover, a number of factors can exert influence on the VPA protein binding such as age, accompanying medications, renal and hepatic diseases, and pregnancy status, which result in large differences between patients in the plasma concentration-to-dose relationship ( Wallenburg et al, 2017 ; Patsalos et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…Patients with inadequate response, doubtful compliance, intercurrent illness, significant comorbidity, presence of interacting medications and so on can benefit from TDM ( Baumann et al, 2004 ; Patsalos et al, 2008 ). The recommended VPA therapeutic range for the epilepsy therapy is 50.0–100 μg/ml and the total concentration is usually measured clinically as a reference for treatment ( Gu et al, 2021 ) , ( Cook et al, 2016 ) .…”

Section: Introductionmentioning

confidence: 99%

Switching Between LC-ESI-MS/MS and EMIT Methods for Routine TDM of Valproic Acid in Pediatric Patients With Epilepsy: What Clinicians and Researchers Need to Know

et al. 2021

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Background: Valproic acid (VPA) is a widely used antiseizure medication and its dosing needs to be tailored individually through therapeutic drug monitoring (TDM) to avoid or prevent toxicity. Currently, immune-enzymatic assays such as Enzyme Multiplied Immunoassay Technique (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Electrospray Ionization Tandem Mass Spectrometry (LC–ESI-MS/MS), resulting a potential lack of concordance between laboratories.Methods: In this study, plasma VPA concentrations were determined for 711 pediatric patients with epilepsy by a routine EMIT assay and by a validated in-house LC-ESI-MS/MS method on the same group of samples, aimed to address the aforementioned concern. Consistency between two assays was evaluated using linear regression and Bland-Altman analysis.Results: The calibration curve was linear in the range of 5.00–300 μg/ml for LC-ESI-MS/MS method and 1.00–150 μg/ml for EMIT assay, respectively. The two methods were proven to be accurate with quality control samples. As a result, a significant correlation between two methods was obtained with a regression equation described as [EMIT]=1.214×[LC−ESI−MS/MS]+3.054 (r2 = 0.9281). Bland-Altman plot showed a mean bias of 14.5 μg/ml (95% confidence interval (CI) (−0.2, 29.2) and a mean increase of 27.8% (95% CI (3.3, 52.4) measured by EMIT assay more than that measured by LC-ESI-MS/MS method.Conclusion: In conclusion, two methods were closely correlated, but EMIT assay overestimate VPA levels in human plasma compared with LC-ESI-MS/MS method. Due to the observed significant discordance between the tested methods, switching from immunoassays to LC-based techniques for TDM of VPA deserves close attention and therapeutic range of 35.0–75.0 μg/ml may be feasible. However, further studies are needed to evaluate the eligibility of this alternative range in the clinical practice. Clinicians should be informed when switching the VPA quantitation methods during the clinical practice.

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Population pharmacokinetics of valproic acid in children with epilepsy: Implications for dose tailoring when switching from oral syrup to sustained‐release tablets

Wang,

Li,

et al. 2024

CPT Pharmacom & Syst Pharma

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Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained‐release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady‐state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20–50 kg. As a result, the PK characteristics of VPA were described using a one‐compartment model with first‐order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h−1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

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Population pharmacokinetics of unbound valproic acid in pediatric epilepsy patients in China: a protein binding model

Cited by 15 publications

References 32 publications

Effects of genetic polymorphism of drug-metabolizing enzymes on the plasma concentrations of antiepileptic drugs in Chinese population

Effects of genetic polymorphism of drug-metabolizing enzymes on the plasma concentrations of antiepileptic drugs in Chinese population

Switching Between LC-ESI-MS/MS and EMIT Methods for Routine TDM of Valproic Acid in Pediatric Patients With Epilepsy: What Clinicians and Researchers Need to Know

Population pharmacokinetics of valproic acid in children with epilepsy: Implications for dose tailoring when switching from oral syrup to sustained‐release tablets

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