Population pharmacokinetic modelling of valproic acid and its selected metabolites in acute VPA poisoning

Jawień, Wojciech; Wilimowska, Jolanta; Kłys, Małgorzata; Piekoszewski, Wojciech

doi:10.1016/j.pharep.2016.12.003

Cited by 13 publications

(15 citation statements)

References 24 publications

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“…One study was conducted in patients with mania . One study was performed in patients with acute VPA poisoning and the other one was conducted in healthy subjects . The sample size of subjects used for model development ranged from 14 to 902.…”

Section: Resultsmentioning

confidence: 99%

“…One study proposed a non‐linear model for VPA pharmacokinetics based on protein binding saturation . One study applied population pharmacokinetics to describe the time course of VPA and its metabolites in an overdose situation . Only seven studies provided an application of the proposed models such as dosage recommendations to achieve target level, simulations of VPA concentrations based on the proposed dosage regimens, and γ‐GT elevation based on VPA dose and SOD2 polymorphism .…”

Section: Resultsmentioning

confidence: 99%

“…Of these, three studies fixed the absorption rate constant (k a ) at literature values . Elimination was characterized as a linear process, with the exception of two studies in which a dose‐dependent maximum effect model (DDE) and a Michaelis–Menten kinetics for β‐oxidation process were employed. NONMEM software was the most frequently used software for population pharmacokinetic model development.…”

Section: Resultsmentioning

confidence: 99%

“…The VPA doses of the included studies ranged from 2.4 to 87.9 mg kg À1 d À1 . Use of sustained-release formulation was reported in nine studies [21,28,31,34,37,38,[40][41][42]. Fluorescence polarization immunoassay (FPIA) and enzyme multiplied immunoassay (EMIT) were used in 57.7% and 15.4% of the studies, respectively.…”

Section: Study Characteristicsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Study Characteristicsmentioning

confidence: 99%

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A systematic review of population pharmacokinetics of valproic acid

Methaneethorn

2018

Brit J Clinical Pharma

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“…Valproic acid (VPA) is an antiepileptic drug (AED) that is used to treat seizures, and the ‘International League against Epilepsy’ as well as other authoritative guidelines recommend VPA as the first choice to treat patients with epilepsy and bipolar disorder. 1 VPA’s therapeutic window is narrow (50–100 µg/mL), and accurate treatment of VPA is challenging because of its individual variability in pharmacokinetics. Therefore, it would be necessary to perform ‘therapeutic drug monitoring (TDM)’, to create an individualised dosing regimen.…”

Section: Introductionmentioning

confidence: 99%

Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model

Guo

Huo

et al. 2020

J Int Med Res

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Objective This prospective study aimed to establish the valproic acid (VPA) population pharmacokinetic model in Chinese patients and realise personalised medication on the basis of population pharmacokinetics. Methods The patients’ clinical information and VPA plasma concentrations were collected from The General Hospital of Taiyuan Iron & Steel (Group) Corporation (TISCO). Nonlinear mixed-effect modelling was used to build the population pharmacokinetic model. To characterise the pharmacokinetic data, a one-compartment pharmacokinetic model with first-order absorption and elimination was used. The first-order conditional estimation with η-ε interaction was applied throughout the model-developing procedure. The absorption rate constant (Ka) was fixed at 2.38 hour−1, and the impact of covariates on clearance and apparent volume of distribution were also explored. Medical records of 60 inpatients were reviewed prospectively and the objective function value (OFV) of the base model and final model were 851.813 and 817.622, respectively. Results Gender was identified as the covariate that had a significant impact on the volume of distribution, and albumin and CYP2C19 genotypes influenced clearance. Conclusion Bootstrap and VPC indicated that a reliable model had been developed that was based on the simulation results, and a simple-to-use dosage regimen table was created to guide clinicians for VPA drug dosing.

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Therapeutic drug monitoring of valproic acid using a dried plasma spot sampling device

Jiang

Cao

et al. 2020

J Mass Spectrom

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Valproic acid (VPA) dosing needs to be individualized for epilepsy patients through therapeutic drug monitoring (TDM). The patients must show up in the clinic at the therapeutic window time to venipuncture sample. Dried plasma spot (DPS) sampling is an alternative way to replace conventional venipuncture sampling. The aim of this study was to develop and validate a DPS-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to monitor VPA in a routine clinical laboratory setting. We compare the DPS with the wet plasma method of clinical samples by LC-MS/MS. The method was linear over the dynamic range of 10-200 μg/ml (covering entire therapeutic range) with a correlation coefficient r 2 ≥ 0.995. Both the DPS and wet plasma methods were fully validated for the accuracy, precision, recovery, and matrix effect. The analyte stability was examined under conditions mimicking the sample storage, transport, and analysis procedures. A clinical study with epilepsy patients receiving VPA (n = 35) showed that, after correction for hematocrit (HCT), plasma concentrations can be successfully calculated from the DPS quantification results. Passing-Bablok regression coefficients showed no proportional bias between estimated and measured plasma concentrations. Similar agreement was found by Bland-Altman plots. The dried sample could be mailed to the clinical lab to test by regular mail service. So DPS can be used for drug monitoring with selfsampling strategy at the patient's convenient time and place specially for ambulatory patients not attending a clinic. K E Y W O R D S dried plasma spot, LC-MS/MS, microsampling strategy, therapeutic drug monitoring, valproic acid 1 | INTRODUCTION Valproic acid (2-propylpentanoic acid, VPA; Figure 1), a branched short-chain fatty acid derivative has been commonly used for the treatment of primary generalized epilepsy, partial seizures, and myoclonic seizures. 1,2 Because epilepsy often coexists with psychiatric illness, VPA has been employed in the treatment of bipolar disorder

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Population pharmacokinetic modelling of valproic acid and its selected metabolites in acute VPA poisoning

Abstract: None of the models perfectly described the experimental data. Important factors like the variable degree of protein binding by VPA could not be included in the models. The small number of subjects used in the study made the analysis of more covariates impossible.

Cited by 13 publications

References 24 publications

A systematic review of population pharmacokinetics of valproic acid

A systematic review of population pharmacokinetics of valproic acid

Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model

Therapeutic drug monitoring of valproic acid using a dried plasma spot sampling device

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