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Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children.

ABSTRACT: AIMS: This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS: The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n= 27) or by mouth as syrup (n= 37). A single cerebrospinal fluid (CSF) sample (n= 60) was collected at the induction of anaesthesia, and plasma samples (n= 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS: Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96l h(-1) 70 kg(-1) . Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (V(ss) ) was 8.1 l 70?kg(-1) . Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS: Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6months, while more research is needed in neonates and in younger infants.

SUBMITTER: Kumpulainen E

PROVIDER: S-EPMC2950990 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children.

Kumpulainen Elina E Välitalo Pyry P Kokki Merja M Lehtonen Marko M Hooker Andrew A Ranta Veli-Pekka VP Kokki Hannu H

British journal of clinical pharmacology 20101001 4

<h4>Aims</h4>This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen.<h4>Methods</h4>The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n= 27) or by mouth as syrup (n= 37). A single cerebrospinal fluid (CSF) sample (n= 60) was collected at the i ...[more]

PMID: 20840447

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Project description:Background: Flurbiprofen axetil is a prodrug that releases the active substance through enzymatic removal of the ester moiety. It is formulated through encapsulation in a lipid microsphere carrier, and widely used to treat perioperative pain. Here, we studied the distribution of R (-)- and S (+)-flurbiprofen in human plasma and cerebrospinal fluid (CSF) after intravenous injection of flurbiprofen axetil. Methods: A total of 70 adult patients undergoing elective lower limb surgery under spinal anesthesia were given a single intravenous injection of 100-mg flurbiprofen axetil. The patients were randomly assigned to 10 groups for plasma and CSF sampling at 10 time points (5-50 min) after subarachnoid puncture and before actual spinal anesthesia. R (-)- and S (+)-flurbiprofen and CSF/plasma ratio were determined by liquid chromatography-tandem mass spectrometry. Results: R (-)-flurbiprofen concentration ranged from 2.01 to 10.9 μg/mL in plasma and 1.46-34.4 ng/mL in CSF. S (+)-flurbiprofen concentration ranged from 1.18 to 10.8 μg/mL in plasma and from 2.53 to 47 ng/mL in CSF. In comparison to S (+)-flurbiprofen, R (-)-flurbiprofen concentration was significantly higher in plasma at all time points (p < 0.05) except at 30 or 40 min, and lower in CSF at all time points (p < 0.05) except at 10, 15 and 40 min. Analysis after correcting drug concentration for body mass index also revealed higher plasma and lower CSF R (-)-flurbiprofen concentration. In comparison to S (+)-flurbiprofen, AUC0-50 for R (-)-flurbiprofen was larger in plasma and smaller in CSF (p < 0.05 for both), and accordingly smaller CSF/plasma AUC0-50 ratio (p < 0.05). There was a positive correlation between R (-)-flurbiprofen concentration and S (+)-flurbiprofen concentration in plasma (r = 0.725, p < 0.001) as well as in CSF (r = 0.718, p < 0.001), and a negative correlation between plasma and CSF concentration of S (+)-flurbiprofen (r = -0.250, p = 0.037), but not R (-)-flurbiprofen. Conclusion: Distribution of R (-)- and S (+)-flurbiprofen in plasma and CSF differed significantly. Penetration of R (-)-flurbiprofen into the CNS was lower than S (+)-flurbiprofen.

Dataset Information

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children.

Publications

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children.

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