| 1. |
- Kumpulainen, Elina, et al.
(författare)
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Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children
- 2010
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 70:4, s. 557-566
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Tidskriftsartikel (refereegranskat)abstract
- Flurbiprofen is a commonly used non-steroidal anti-inflammatory drug in children to treat pain and fever. There is limited information on the pharmacokinetics of flurbiprofen in children and no data on the cerebrospinal fluid permeation of flurbiprofen. WHAT THIS STUDY ADDS Our population pharmacokinetic model indicates that weight-based dosing of flurbiprofen is appropriate in children older than 6 months. The bioavailability of oral flurbiprofen syrup is high, 71-91%, and thus, the oral syrup provides accurate dosing in paediatric patients. Cerebrospinal fluid concentrations of flurbiprofen are markedly higher than the unbound plasma concentrations. 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 0.96 l 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 6 months, while more research is needed in neonates and in younger infants.
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| 2. |
- Valitalo, Pyry, et al.
(författare)
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Maturation of Oxycodone Pharmacokinetics in Neonates and Infants : a Population Pharmacokinetic Model of Three Clinical Trials
- 2017
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Ingår i: Pharmaceutical research. - : SPRINGER/PLENUM PUBLISHERS. - 0724-8741 .- 1573-904X. ; 34:5, s. 1125-1133
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim of the current population pharmacokinetic study was to quantify oxycodone pharmacokinetics in children ranging from preterm neonates to children up to 7 years of age. Methods Data on intravenous or intramuscular oxycodone administration were obtained from three previously published studies (n = 119). The median [range] postmenstrual age of the subjects was 299 days [170 days-7.8 years]. A population pharmacokinetic model was built using 781 measurements of oxycodone plasma concentration. The model was used to simulate repeated intravenous oxycodone administration in four representative infants covering the age range from an extremely preterm neonate to 1-year old infant. Results The rapid maturation of oxycodone clearance was best described with combined allometric scaling and maturation function. Central and peripheral volumes of distribution were nonlinearly related to bodyweight. The simulations on repeated intravenous administration in virtual patients indicated that oxycodone plasma concentration can be kept between 10 and 50 ng/ml with a high probability when the maintenance dose is calculated using the typical clearance and the dose interval is 4 h. Conclustions Oxycodone clearance matures rapidly after birth, and between-subject variability is pronounced in neonates. The pharmacokinetic model developed may be used to evaluate different multiple dosing regimens, but the safety of repeated doses should be ensured.
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| 3. |
- Välitalo, Pyry, et al.
(författare)
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Plasma and Cerebrospinal Fluid Pharmacokinetics of Naproxen in Children
- 2012
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 52:10, s. 1516-1526
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L/70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age.
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