当前位置： SCI文献检索 > EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY期刊下所有文献 > A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy.

A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy.

Abstract：

PURPOSE:The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100 mg/L). METHODS:Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg. RESULTS:A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. CONCLUSIONS:If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.

journal_name

Eur J Clin Pharmacol

journal_title

European journal of clinical pharmacology

authors

Rodrigues C,Chhun S,Chiron C,Dulac O,Rey E,Pons G,Jullien V

doi

10.1007/s00228-018-2444-2

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

793-803

issue

6

eissn

0031-6970

issn

1432-1041

pii

10.1007/s00228-018-2444-2

journal_volume

74

pub_type

杂志文章

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