No abstract

No abstract

BackgroundNearly half of children with Down Syn-drome (DS) who undergo cardiac surgery, receive parac-etamol as part of their post-operative pain treatment (Fudge et al., 2010). Differences have been reported in paracetamol metabolism in children with or without DS (Griener et al., 1990). The aim of the study was to deter-mine the population pharmacokinetics of intravenous paracetamol after cardiac surgery and the elimination through the major metabolic pathways in two groups of children – those with and those without DS.MethodsThe model was based on 483 plasma sam-ples from 30 children of whom 17 (median age 176 days [92-300] and bodyweight 6.1 kg [4.2–12.9]) had DS and 13 (median age 204 days [105-944] and bodyweight 5.9 kg[4.0–8.2]) did not. All received three paracetamol dos-es of 7.5 mg/kg (<10 kg) or 15 mg/kg (>10 kg) at 8 hour-ly intervals. Population pharmacokinetic modelling for paracetamol, paracetamol-sulfate and paracetamol-glu-curonide was performed using NONMEM 7.2. One, two and three compartment models were evaluated and the influence of different covariates such as age, bodyweight, cardiopulmonary bypass time and DS was investigated. Model selection criteria were statistical significant de-crease in objective function and evaluation of diagnostic plots.ResultsAll compounds were best described with a one-compartment model, in which clearance (Cl) in-creased linearly with bodyweight. Volume of distribution (Vd) was not statistical significantly influenced by any covariates. The population value [relative standard er-ror] for paracetamol Cl and Vd were (27.6 ml/min/6.1 kg [22%]) and (7560 ml/6.1 kg [19%]) respectively. For parac-etamol-sulfate and paracetamol-glucuronide Cl and Vd were 23 [29%] and 1590 [33%], and 68.1 [25%] and 5330 [7%] respectively. DS did not have a statistically significant influence on any model parameter for any of the com-pounds.ConclusionPopulation pharmacokinetic analysis re-vealed that bodyweight influenced clearance of parac-etamol, paracetamol-sulfate and paracetamol-glucuro-nide in children from 3–36 months of age. However, no statistically significant differences in any of the pharma-cokinetic parameters of paracetamol between children with and without DS after cardiac surgery were observed. As paracetamol is also metabolised through cytochrome P450 2E1 oxidation, the following step will be to incorpo-rate these metabolites in this model to evaluate potential differences in paracetamol metabolism between children with or without DS.

BackgroundAminoglycosides are administered to treat (suspected) neonatal sepsis. The pharmacokinetics (PK) of this antibiotic class are expected to be different in neonates with perinatal asphyxia (PA) treated with therapeutic hypothermia (TH). Effective exposure of the aminoglycoside amikacin in neonates is achieved using a prospectively validated population PK mod-el-derived dosing regimen.1 However, dosing adjust-ments in case of PA with TH are lacking. The aim of the current (AMICOOL) study was to further explore amikacin disposition in neonates by quantifying the impact of PA treated with TH on amikacin clearance and to provide dosing recommendations for this specific patient population.MethodsAmikacin therapeutic drug monitoring data were retrospectively collected from term neonates with PA treated with TH and admitted to the neonatal inten-sive care units of VUmc Amsterdam and the University Hospitals Leuven between 2010–2015. Data were added to the original published amikacin population PK dataset.2 A data-driven covariate analysis was performed to assess the impact of PA treated with TH on amikacin clearance. Monte Carlo simulations facilitated the comparison of simulated amikacin exposures using the current dosing guidelines.1 and proposed dosing adaptations for PA treated with TH. We hereby aimed to achieve optimal amikacin trough (<5 mg/L) and peak (>24 mg/L) levels. Stochastic simulations were used to investigate the differ-ences in exposure among typical neonates with PA and TH with varying birth weights (1965–4220 g).ResultsData of 55 neonates with PA treated with TH were added to the original amikacin population PK dataset of 930 neonates.2 A 40.6% (RSE 9%) decrease in amikacin clearance for neonates with PA with TH was documented. Based on Monte Carlo simulations, the current dosing guidelines resulted in 40%–57% of neonates with PA and TH displaying amikacin trough concentrations above the toxic trough level (>5 mg/L), while an additional increase of the dosing interval with 12 hours decreased this percentage to 14%. Stochastic simulations showed that among typical neonates the percentage of patients with trough concentrations>5 mg/L ranges 14% to 25%.ConclusionIn neonates with perinatal asphyxia treated with therapeutic hypothermia, amikacin clearance is reduced with 40.6%. Based on simulations, an additional prolongation of the dosing interval with 12 hours results in optimised amikacin exposure and reduces toxicity in this specific population. As a future perspective, the model-based dosing proposal needs prospective validation. Since amikacin can be used as a surrogate for glomerular filtration, clearance of other drugs using the same elimination route could also be reduced in case of perinatal asphyxia treated with therapeutic hypothermia and may require further dosing adaptations.