A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy: A Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation

Ding, Junjie; Wang, Yi; Wang, Lin; Wang, Changlian; Zhao, Limei; Li, Xingang; Zhao, Zhigang; Miao, Liyan; Jiao, Zheng

doi:10.1007/s40262-014-0212-8

Cited by 62 publications

(85 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Table summarizes the characteristics of each study. Most of the models were developed in patients with epilepsy . One study reported a model incorporating data from both epileptic and psychiatric patients .…”

Section: Resultsmentioning

confidence: 99%

“…To better characterize this non‐linearity, Ding et al . compared the ability of three models (i.e. the power exponent model, the dose dependent maximum effect (DDE) model and the protein binding model).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a TDM effect could be another factor contributing to the increased CL VPA since individuals with high CL VPA tend to receive a higher dose. To better characterize this non-linearity, Ding et al [37] compared the ability of three models (i.e. the power exponent model, the dose dependent maximum effect (DDE) model and the protein binding model).…”

Section: Discussionmentioning

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%

See 3 more Smart Citations

A systematic review of population pharmacokinetics of valproic acid

Methaneethorn

2018

Brit J Clinical Pharma

View full text Add to dashboard Cite

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

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Study Characteristicsmentioning

confidence: 99%

See 2 more Smart Citations

A systematic review of population pharmacokinetics of valproic acid

Methaneethorn

2018

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…We identified 11 nonlinear mixed-effects models published between 1995 and 2015 in the literature. [7][8][9]16,[24][25][26][27][28][29][30] Table 1 describes the pharmacokinetic parameters of each model. Four models 27 The volume of distribution was estimated in models E, I, J, and K, whereas it was fixed or not reported in other studies.…”

Section: Population Pharmacokinetic Models Usedmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Population Pharmacokinetics and Pharmacodynamics of Norvancomycin in Children With Malignant Hematological Disease

Wang

et al. 2020

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Knowledge of pharmacokinetic (PK) behavior of norvancomycin (NVCM) in pediatric patients is lacking, which leads to empirical therapy in clinical practice. This study developed a population PK model of children aged 0‐15 years; 112 opportunistic samples in total from 90 children were analyzed. The stability and prediction of the final model were evaluated by goodness‐of‐fit plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. The PKs of NVCM in children was described by a 2‐compartment model with first‐order elimination along with body weight and estimated glomerular filtration rate as significant covariates on clearance. The population typical values of the PK parameters were as follows: clearance 0.12 L/kg/h, central compartment distribution volume 0.17 L/kg, peripheral compartment distribution volume 0.38 L/kg, and intercompartmental clearance 0.35 L/kg/h. Logistic analysis showed that the ratio of area under the concentration‐time curve over 24 hours (AUC0‐24) to minimum inhibitory concentration (MIC) had the strongest correlation with clinical efficacy, and at least 80% clinical efficiency could be achieved when AUC0‐24/MIC ≥ 221.06 was defined as the target. Monte Carlo simulation results suggested that a higher dose was required for this pediatric population in order to reach the target. The dosing regimen was optimized based on the final model. A population PK model of NVCM was first characterized in children with hematologic malignancy, and an evidence‐based approach for NVCM dosage individualization was provided.

show abstract

A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy: A Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation

Abstract: The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

Cited by 62 publications

References 47 publications

A systematic review of population pharmacokinetics of valproic acid

A systematic review of population pharmacokinetics of valproic acid

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

Population Pharmacokinetics and Pharmacodynamics of Norvancomycin in Children With Malignant Hematological Disease

Contact Info

Product

Resources

About