Trial reportEuropean journal of clinical pharmacology2015
Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants.
Trial report in European journal of clinical pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
14 citing papers in PubMed, 36 citations in OpenAlex.
- Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants.Pediatric research · 2017Trial
- Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model.Clinical pharmacokinetics · 2016Trial
- Acetaminophen causes neurodevelopmental injury in susceptible babies and children: no valid rationale for controversy.Clinical and experimental pediatrics · 2024Article
- Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation.Pharmaceutical research · 2023Article
- Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper.British journal of clinical pharmacology · 2022Review
- The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children.Frontiers in pharmacology · 2022Article
- Integration of Placental Transfer in a Fetal-Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus.Clinical pharmacokinetics · 2020Article
- Acetaminophen increases pulmonary and systemic vasomotor tone in the newborn rat.Pediatric research · 2020Article
- A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates.Frontiers in pediatrics · 2020Review
- Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study.BMJ paediatrics open · 2019Article
- Intensive and prolonged urine collection in preterm infants reveals three distinct indomethacin metabolic patterns: potential implications for drug dosing.Pediatric research · 2018Article
- Article
- Neonatal pain management: still in search for the Holy Grail.International journal of clinical pharmacology and therapeutics · 2016Review
- Population pharmacokinetics of riociguat and its metabolite in patients with chronic thromboembolic pulmonary hypertension from routine clinical practice.Pulmonary circulationArticle
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeBased on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach.
methodsA population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses.
resultsParacetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg(1.4), which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both metabolites was estimated to be 11.4 times higher than the excretion rate constant of unchanged paracetamol, yielding values of 0.580 mL/min/kg. Developmental changes were best described by bodyweight in linear relationships on the distribution volumes, the formation of paracetamol-glucuronide and the unchanged excretion of paracetamol, and in an exponential relationship on the formation of paracetamol-sulphate. There was no evidence for up-regulation or other time-varying changes in any of the model parameters. Simulations with this model illustrate how paracetamol-glucuronide recovery in urine increases over time due to the slower formation of this metabolite and in the absence of up-regulation.
conclusionsDevelopmental changes, described by bodyweight-based functions, rather than up-regulation, explain developmental changes in paracetamol disposition in neonates and infants.
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