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O-15 Population pharmacokinetic modelling of paracetamol and its two major metabolites after cardiac surgery in children with and without down syndrome
  1. Mian1,
  2. Valkenburg1,
  3. Allegaert2,
  4. Koch3,
  5. Breatnach4,
  6. Knibbe5,
  7. Tibboel1,
  8. Krekels6
  1. 1Erasmus-MC Sophia Children’s Hospital, ROTTERDAM, Netherlands
  2. 2Department of Development and Regeneration KU Leuven, LEUVEN, Belgium
  3. 3Department of Hospital Pharmacy Erasmus MC, ROTTERDAM, Netherlands
  4. 4Department of Anaesthesia and Critical Care medicine Our Lady’s Children’s Hosp., DUBLIN, Ireland
  5. 5Department of Clinical Pharmacy St. Antonius Hospital, NIEUWEGEIN, Netherlands
  6. 6Division of pharmacology, LACDR, LEIDEN, Netherlands

Abstract

Background Nearly 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.

Methods The 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.

Results All 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.

Conclusion Population 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.

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