A systematic review of population pharmacokinetics of valproic acid

Methaneethorn, Janthima

doi:10.1111/bcp.13510

Cited by 75 publications

(86 citation statements)

References 50 publications

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“…Several models have been published in the pediatric population, either to describe valproate pharmacokinetics or to predict concentrations. 21 The challenge is to know which model among all published might correspond to our population and could be used in clinical practice. External validation of PPK models uses data collected from a new patient cohort receiving a drug.…”

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confidence: 99%

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Tauzin

Tréluyer

Nabbout

et al. 2018

The Journal of Clinical Pharma

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Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128 mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6 mg/L and a root mean squared error of 25.1 mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50 mg/L. Simulations suggested increasing doses, especially for children ࣘ40 kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight.

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confidence: 99%

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Tauzin

Tréluyer

Nabbout

et al. 2018

The Journal of Clinical Pharma

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“…Most of them had a one-compartment model structure developed based on TDM data. A systematic review of population pharmacokinetics of valproic acid reported that only 65% of the developed models were evaluated for their performance and appropriateness (eg, bootstrap analysis, goodness of fit plots, predictive check) 22. Additionally, the United States Food and Drug Administration suggested that external evaluation of a population pharmacokinetic model is the most stringent method for assessment of a developed model 1.…”

Section: Discussionmentioning

confidence: 99%

External evaluation of a published population pharmacokinetic model of valproic acid in Thai manic patients

Methaneethorn

Lohitnavy

2018

Eur J Hosp Pharm

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ObjectiveTo evaluate external predictability of a population pharmacokinetic model of valproic acid in Thai patients with mania to ensure its appropriateness for use in other clinical settings.MethodsThe published population pharmacokinetic model was evaluated for its predictive ability (at both individual and population levels) and its precision by means of mean absolute prediction error (MAPE), root mean square error (RMSE) and normalised prediction distribution error (NPDE).ResultsForty-six steady-state serum valproic acid concentration levels from 30 manic patients were retrospectively collected from routine therapeutic drug monitoring at Srithanya Hospital, Thailand. For the prediction-based diagnostics, the MAPE and RMSE were 10.44% (95% CI 8.12% to 12.76%) and 12.99% (95% CI 9.51% to 15.72%), respectively, suggesting that the proposed model was relatively predictive and had a good precision. In simulation-based diagnostics, the NPDE results also showed that the model appropriately predicted valproic acid concentration levels, as indicated by a normal distribution of NPDEs with a mean and a variance of 0 and 1, respectively.ConclusionThe predictability of the population pharmacokinetic model of valproic acid in Thai patients with mania was confirmed. This model could be applied in other clinical settings.

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“…Valproic acid (VPA) is effective for the prevention of various seizures, and it is widely used in the developing world as it is inexpensive. 3 The adverse effects of VPA include vomiting, nausea, and sleepiness. More seriously, the risk of liver damage induced by VPA is presented time-and dose-dependently.…”

Section: Funding Informationmentioning

confidence: 99%

“…The principal therapy of epilepsy is daily antiepileptic drugs for the entire life. Valproic acid (VPA) is effective for the prevention of various seizures, and it is widely used in the developing world as it is inexpensive . The adverse effects of VPA include vomiting, nausea, and sleepiness.…”

Section: Introductionmentioning

confidence: 99%

Potential biomarker of fibroblast growth factor 21 in valproic acid‐treated livers

Guo

Liang

et al. 2019

BioFactors

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Background Valproic acid (VPA) is a clinical medicine primarily prescribed to control epileptic symptoms. VPA has potential side‐effects, such as hepatotoxicity. Fibroblast growth factor 21 (FGF21) is a functional cytokine for metabolic regulation. In this article, we aimed to evaluate the possible clinical application of FGF21 in VPA‐treated livers in early undetected liver injury (EULI). Methods Methodologically, plasma samples of VPA‐treated epileptic patients were isolated for biochemical and high‐performance liquid chromatography tests. In addition, VPA‐dosed mice were subjected to determinations of serological parameters, key regulatory effectors and FGF21 expressions through biochemical analyses, enzyme‐linked immunosorbent assay, immunohistochemistry stain, immunofluorescence stain, and reverse transcription‐polymerase chain reaction (RT‐PCR) test, respectively. Results The serological data suggested that VPA‐treated epileptic patients showed visibly elevated FGF21 contents in plasma samples. However, other diagnostic parameters showed inconspicuous changes. As revealed in animal study, VPA‐dosed mice exhibited undetected morphological alterations and hormonal changes in the liver, pancreas, and kidneys. Furthermore, serological parameters and key regulatory proteins in VPA‐dosed livers and controls showed inconspicuous changes. Interestingly, endogenous FGF21 expressions in VPA‐dosed mice were increased in sera. In further experiments, the findings showed that intracellular expressions of FGF21 mRNA and protein were upregulated in VPA‐dosed livers as revealed in RT‐PCR and immunoassay. Conclusions Taken together, these preliminary data reveal that functional FGF21 cytokine may serve as a potent predictor in VPA‐related EULI.

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A systematic review of population pharmacokinetics of valproic acid

Cited by 75 publications

References 50 publications

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

External evaluation of a published population pharmacokinetic model of valproic acid in Thai manic patients

Potential biomarker of fibroblast growth factor 21 in valproic acid‐treated livers

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