Pharmacokinetic interaction between valproic acid and phenobarbital

Pokrajac, M.; Miljković, Branislava; Varagić, V.M.; Lević, Z

doi:10.1002/bdd.2510140108

Cited by 11 publications

(4 citation statements)

References 12 publications

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“…Appraisal of 4‐ene‐VPA model in children was, thus, not feasible. Nonetheless, simulations of either pediatric or adult VPA plasma concentrations in the present study were in good agreement with respective real‐world data 20,23,29–37 . Use of the observed data‐verified adult 4‐ene‐VPA model established herein would be a justified approach in estimating pediatric 4‐ene‐VPA levels 38,39 .…”

Section: Discussionsupporting

confidence: 75%

“…Nonetheless, simulations of either pediatric or adult VPA plasma concentrations in the present study were in good agreement with respective real-world data. 20,23,[29][30][31][32][33][34][35][36][37] Use of the observed data-verified adult 4-ene-VPA model established herein would be a justified approach in estimating pediatric 4-ene-VPA levels. 38,39 Certainly, unidentified S3, of VPA (recommended therapeutic range: 50-100 mg/L) and its metabolite 4-ene-VPA (reported toxic level:…”

Section: Discussionmentioning

confidence: 91%

“…Nonetheless, simulations of either pediatric or adult VPA plasma concentrations in the present study were in good agreement with respective real‐world data. 20 , 23 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 Use of the observed data‐verified adult 4‐ene‐VPA model established herein would be a justified approach in estimating pediatric 4‐ene‐VPA levels. 38 , 39 Certainly, unidentified cryptic factors affecting absorption, distribution, metabolism, and excretion of VPA or 4‐ene‐VPA in small children remain to be uncovered through clinical studies and real‐data collection to facilitate precision dosing.…”

Section: Discussionmentioning

confidence: 92%

“…Inputs for the demographics of the virtual populations were made to be as close as possible to the information in the literature with respect to age range, male–female ratio, and dosing regimens (Table 1 ). 20 , 23 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 …”

Section: Methodsmentioning

confidence: 99%

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Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact

Huang,

Kung

et al. 2023

CPT Pharmacom & Syst Pharma

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The anticonvulsant valproic acid (VPA) despite complex pharmacokinetics has been in clinical use for nearly six decades. Previous reports indicated neonates, infants, and toddlers/preschoolers had higher risk of valproate hepatotoxicity than adults. However, dosing recommendations for those less than ten years of age are lacking. To decipher clinical puzzles, physiologically based pharmacokinetics (PBPK) models of VPA and its hepatotoxic metabolite 4‐ene‐VPA were constructed and simulated with particularly integrated information of drug‐metabolizing enzyme ontogeny. Adult and pediatric PK data of VPA (n = 143 subjects) and 4‐ene‐VPA (n = 8 subjects) collected from previous reports were used for model development and validation. Sensitivity analyses were performed to characterize ontogeny impacts of CYP2C9 and UGT2B7 on dispositions of VPA and 4‐ene‐VPA across age groups. Optimal VPA dosing for each pediatric age group was also predicted and objectively judged by ensuring VPA efficacy and avoiding 4‐ene‐VPA hepatotoxicity. The study revealed UGT2B7 ontogeny was quite influential on VPA clearance even in neonates and small children. Intrinsic clearance of CYP2C9 was the most prominent determinant for AUCs of VPA and 4‐ene‐VPA in infants, and toddlers and preschoolers, reflecting higher hepatotoxicity risk due to noxious 4‐ene‐VPA accumulation in these groups. The ontogeny‐based PBPK approach complements conventional allometric methods in dosing estimation for the young by providing more mechanistic insight of the processes changing with age. The established ontogeny‐based PBPK approach for VPA therapy deserves further corroboration by real‐world therapeutic data to affirm its clinical applicability.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact

Huang,

Kung

et al. 2023

CPT Pharmacom & Syst Pharma

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Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data

Blanco‐Serrano

Otero

Santos-Buelga

et al. 1999

Biopharm. Drug Dispos.

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The aim of the present study was to estimate valproic acid (VPA) clearance values for adult patients with epilepsy, using serum concentrations gathered during their routine clinical care. Retrospective steady state serum concentrations data (n=534) collected from 208 adult patients receiving VPA were studied. Data were analysed according to a one‐compartment model using the NONMEM program. The influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) were investigated. The results of the population pharmacokinetics analysis were validated in a group of 30 epileptic patients. The final regression model for VPA clearance (Cl) was: The inter‐individual variability in VPA clearance, described by a proportional error model, had a variation coefficient (CV) of 23.4% and the residual variability, described using an additive model, was 11.4 mg/L. These results show that VPA clearance increased linearly with TBW, but increases nonlinearly with increasing VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a significant increase in VPA clearance. The model predictions in the validation group were found to have satisfactory precision and bias. In conclusion, inter‐individual variability in VPA clearance can be partly explained by TBW, daily dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this variability to be reduced by 37.23% which may be very useful for clinicians when establishing the initial VPA dosage regimen. However, the magnitude of inter‐individual plus residual variabilities, remaining in the final model, render these dosage predictions imprecise and justify the need for VPA serum level monitoring in order to individualize dosage regimens more accurately. Copyright © 1999 John Wiley & Sons, Ltd.

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Pharmacokinetic variability of phenobarbital: a systematic review of population pharmacokinetic analysis

Methaneethorn

Leelakanok

2020

Eur J Clin Pharmacol

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Pharmacokinetic interaction between valproic acid and phenobarbital

Cited by 11 publications

References 12 publications

Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact

Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact

Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data

Pharmacokinetic variability of phenobarbital: a systematic review of population pharmacokinetic analysis

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