Although the principles of drug disposition also apply in neonates, their specific characteristics warrant focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Besides maturational aspects of drug absorption and distribution, maturation mainly relates to (renal) elimination and (hepatic) metabolic clearance. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite the overall low clearance, interindividual variability is already extensive and can be predicted by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor, growth restriction or peripartal asphyxia. These findings are illustrated by observations on amikacin and vancomycin. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetic characteristics. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. The impact of covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or 'probe' drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. The description of a compound specific pattern is beyond compound specific relevance. The maturational patterns described and the extent of the impact of covariates can subsequently be applied to predict in vivo time-concentration profiles for compounds that undergo similar routes of elimination. Through improved predictability, such maturational models can serve to improve both the clinical care and feasibility and safety of clinical studies in neonates.
AIMA recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered. METHODSPopulation PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10-15 weeks post-partum. RESULTSPopulation PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h -1 ) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h ). In contrast, there was no difference in clearance to paracetamol sulphate. CONCLUSIONThe increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• In adults, paracetamol is almost exclusively metabolized by the hepatic route and excreted into urine, with paracetamol glucuronide (47-62%) and paracetamol sulphate (25-36%) as the main metabolites. Between 8-10% of the paracetamol dose is oxidized by cytochrome P450 (CYP2E1) into 3-hydroxy-paracetamol and the toxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI), while only 1-4% is excreted in urine as unchanged paracetamol.• Total clearance of paracetamol appears higher at Caesarean delivery compared with healthy female volunteers but it is unknown which pathways are affected. WHAT THIS STUDY ADDS• Population pharmacokinetic modelling showed a substantially higher paracetamol clearance in women at delivery compared with a subset of the same women 12 weeks post-partum.• The increase in total paracetamol clearance at delivery is due to a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance.• Compared with modelling based on metabolite fractions retrieved in urine only, population modelling based on both plasma and urine collections was of added value to gain insight into how different metabolic pathways of paracetamol contribute to changes in total clearance.
Unintended PG administration (34 mg/kg/24 h) for a maximum of 48 h seems to be tolerated in (pre)term neonates and does not affect short-term postnatal adaptations. Further studies on PG disposition and the level of safe exposure to PG, including long-term safety data in neonates are needed.
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