Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors

Xu, Shoufang; Chen, Yanan; Zhao, Mingming; Guo, Yingjie; Wang, Zhan-You; Zhao, Limei

doi:10.1016/j.ejps.2018.06.033

Cited by 28 publications

(26 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To date, the reported Kas of VPA are, respectively, 2.38 hour À1 , 10 2.64 hour À1 , 3,7 and 1.9 hour À1 . 4,20,21 We tried all of them in the modelling process, and the goodness-of-fit was best when Ka was fixed to 2.38 hour À1 . Furthermore, this value was estimated Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…A summary of the reports that were published over the past 5 years on the covariates that affect VPA concentration is presented ( Table S1 ). Most reports used PPK, 1 , 4 , 5 , 7 , 16 – 19 whilst only one report intensively collected samples in adults using the two-compartment model. 1 Both had sparse pharmacokinetic data and were fitted using a one-compartment model.…”

Section: Discussionmentioning

confidence: 99%

“…To date, the reported Kas of VPA are, respectively, 2.38 hour −1 , 10 2.64 hour −1 , 3 , 7 and 1.9 hour −1 . 4 , 20 , 21 We tried all of them in the modelling process, and the goodness-of-fit was best when Ka was fixed to 2.38 hour −1 . Furthermore, this value was estimated based on the Chinese population and we used immediate release tablets/solutions instead of sustained-release tablets in this research, and thus, we thought that this was suitable for our pharmacokinetic data.…”

Section: Discussionmentioning

confidence: 99%

“…Various studies have demonstrated that CYP2C19 genetic variations play a vital role in VPA plasma concentration variability in both paediatric and adult patients. 4 …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Various studies have demonstrated that CYP2C19 genetic variations play a vital role in VPA plasma concentration variability in both paediatric and adult patients. 4 …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

“…This interaction is triggered by inhibition of acylpeptide hydrolase (APEH) activity with meropenem. The study of VPA-d6 β-D-glucuronide (VPA-G) concentration in APEH rs3816877 and rs1131095 carriers revealed that patients with the APEH rs3816877 C/C genotype show higher levels than C/T carriers in the Chinese population [283]. Valproate-related neuroprotection in experimentally triggered epileptic seizures has been associated with PKC-dependent GABAAR γ2 phosphorylation at serine 327 residue [284].…”

Section: Epilepsymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

View full text Add to dashboard Cite

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

show abstract

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

View full text Add to dashboard Cite

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.

show abstract

Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors

Cited by 28 publications

References 83 publications

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

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

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

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

Contact Info

Product

Resources

About