Plasma and Cerebrospinal Fluid Pharmacokinetics of Naproxen in Children
P. Välitalo[1], E. Kumpulainen[1], M. Manner [1], M. Laisalmi[2], M. Lehtonen[1], A. Hooker[3], V-P. Ranta[1], H. Kokki[2]
1. Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland 2. Department of Anesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland 3. Department of Pharmaceutical Biosciences, University of Uppsala, Uppsala, Sweden
Objectives: There has recently been interest in the mechanism of action of NSAIDs in CNS. We evaluated the cerebrospinal fluid (CSF) penetration of naproxen in children undergoing lower body surgery in spinal anaesthesia. Also, while there have been studies of naproxen pharmacokinetics in children, none of the studies have investigated the pharmacokinetics of naproxen in children younger than 5 years [1]. We estimated the pharmacokinetics of naproxen in 51 children aged 3 months to 13 years.
Methods: 53 children were enrolled in the study. The children received 10 mg/kg dose of oral naproxen suspension. 270 total plasma concentrations, 52 unbound plasma concentrations and 52 CSF concentrations were analyzed and included in the data. Modeling was performed with NONMEM VI 2.0 and PsN 2.3.2 [2]. To describe the distribution and accumulation of naproxen into CSF, an intercompartmental clearance QCSF and an uptake factor UPTK were estimated. The case-deletion diagnostics feature of PsN was used to detect potential outliers in the dataset.
Results: The plasma data were best described with a 2-compartmental model with first-order absorption. Some individuals had remarkably low concentrations of naproxen. Case-deletion diagnostics identified two individuals with Cook score >1 and covariance ratio <0.4. These individuals were removed from the final analysis.
Bodyweight predicted plasma clearance of naproxen linearly (with an exponent of 1), and age did not seem to affect the clearance after weight had been included as a covariate. When scaled to 70kg, the apparent clearance of naproxen was 0.59 l/h and the apparent volumes of distribution were 7.4 l and 4.4 l for central and peripheral volumes, respectively.
The CSF uptake factor UPTK was 7.8 (20 % RSE). The fraction of unbound naproxen in plasma was 0.14% (7.9 % RSE).
Conclusions: The concentrations of naproxen in CSF are markedly greater than the concentrations of unbound naproxen in plasma. This is probably a result of protein binding in CSF, and is typical for lipophilic drugs with high protein binding [3].
References:
[1] Ansell B, Hanna D, Stoppard M. Naproxen absorption in children. Curr med Res Opin. 1975, 3(1): p. 46-50
[2] Lindbom L, Pihlgren P, Jonsson N. PsN-Toolkit—A collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed, 2005. 79(3): p. 241-257
[3] Shen D, Artru A, Adkison K. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv Drug Deliv Rev, 2004. 56(12): p. 1825-57.
