CSF and Plasma Pharmacokinetics of Flurbiprofen in Children
P Välitalo[1], E. Kumpulainen[1], M. Laisalmi[2], M. Lehtonen[1], A. Hooker[3], V-P. Ranta[1], H. Kokki[1,2]
1. University of Kuopio, Kuopio, Finland 2. Kuopio University Hospital, Kuopio, Finland 3. University of Uppsala, Uppsala, Sweden
Objectives: There has recently been interest in mechanism of action of NSAIDs in CNS. We have evaluated the CNS penetration of flurbiprofen in children undergoing lower body surgery in spinal anaesthesia. We also estimated the pharmacokinetics of flurbiprofen in children aged 3 months to 13 years, and estimated the absolute bioavailability of flurbiprofen in children. Previously, there has been only one study of flurbiprofen pharmacokinetics in children aged 6-12 years and no absolute bioavailability was estimated in that study [1].
Methods: 64 children aged 3 months to 13 years were enrolled in the study. 27 of the children received intravenous dose of flurbiprofen axetil corresponding to circa 0.65 mg/kg of flurbiprofen. 37 of the children received 1 mg/kg of oral flurbiprofen syrup. 304 total plasma concentrations, 62 unbound plasma concentrations and 60 total CSF concentrations were analyzed and included in the data. Modeling was performed with NONMEM VI 2.0. For flurbiprofen distribution into CSF, an intercompartmental clearance QCSF was estimated. The volume of CSF reported in literature was used as Vd(CSF). The rate constant of flurbiprofen transfer from central compartment V(central) to CSF was calculated as QCSF/V(central), multiplied by fraction unbound in plasma and multiplied by “uptake factor”.
Results: In raw data, flurbiprofen concentrations in CSF were about sevenfold compared to unbound flurbiprofen in plasma. Hence, the “uptake factor” estimated for CSF kinetics was 6.8 (+-0.070 RSE). The fraction unbound of flurbiprofen in plasma was 0.0314% (+- 0.043 RSE). The oral bioavailability of flurbiprofen was 0.8 and CYP maturation did not seem to affect elimination rate of flurbiprofen in infants. Weight alone was an adequate covariate for clearance.
Conclusions: Flurbiprofen enters CSF readily. The reason for flurbiprofen concentrations in CSF being higher than free lurbiprofen in plasma is likely a result of protein binding or active uptake. Typically, lipophilic drugs with extensive protein binding have CSF concentrations higher than unbound plasma concentrations [2].
References:
[1] Scaroni C, Mazzoni PL, D’Amico E, Benvenuti C, Hind ID. Pharmacokinetics of oral and rectal flurbiprofen in Children. Eur J Clin Pharmacol, 1984. 27: p. 367-369.
[2] 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.
