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Cited by 240Pharmaceutical studies and practicesAntibiotics Pharmacokinetics and EfficacyAnesthesia and Sedative Agents

Acetaminophen Developmental Pharmacokinetics in Premature Neonates and Infants: A Pooled Population Analysis

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Anderson, Brian J., van Lingen, Richard A., Hansen, Tom G., Lin, Yuan-Chi, Holford, Nicholas H. G.·2002·Anesthesiology
DOI 10.1097/00000542-200206000-00012
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Abstract

Background: The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens. Methods: A population pharmacokinetic analysis of acetaminophen time-concentration profiles in 283 children (124 aged < or = 6 months) reported in six studies was undertaken using nonlinear mixed-effects models. Neonates and infants were given either single or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 months was 1 day (range, birth to 6 months), median postconception age was 40 weeks (range, 28-64 weeks), and median weight was 3.1 kg (range, 1.2-9.0 kg). Results: Population pharmacokinetic parameter estimates and their variability (percent) for a one-compartment model with first-order input, lag time, and first-order elimination were as follows: volume of distribution, 66.6 l (20%); clearance, 12.5 l/h (44%); standardized to a 70-kg person using allometric "1/4 power" models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 weeks from 109.7 l/70 kg at 28 weeks after conception to 72.9 l/70 kg by 60 weeks. Clearance increased from 28 weeks after conception (0.74 l x h(-1) x 70 kg(-1)) with a maturation half-life of 11.3 weeks to reach 10.8 l x h(-1) x 70 kg(-1) by 60 weeks. The absorption half-life for the oral elixir preparation was 0.21 h (120%) with a lag time of 0.42 h (70%), but absorption was further delayed (2 h) in premature neonates in the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 h (100%) and 1.4 h (57%), respectively. The absorption half-life for the rectal solution was 0.33 h. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 weeks after conception to 0.86 at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 weeks postconception to 0.5 at 2 yr of age. The relative bioavailability of the rectal solution was 0.66. Conclusions: A mean steady state target concentration greater than 10 mg/l at trough can be achieved by an oral dose of 25 mg x kg(-1) x d(-1) in premature neonates at 30 weeks' postconception, 45 mg x kg(-1) x d(-1) at 34 weeks' gestation, 60 mg x kg(-1) x d(-1) at term, and 90 mg x kg(-1) x d(-1) at 6 months of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be achieved with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg. kg-1. d-1 in premature neonates at 30 weeks' gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg x kg(-1) x d(-1) at 6 months. These regimens may cause hepatotoxicity in some individuals if used for longer than 2-3 days.

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  • Paracetamol distributes widely in body fluids and has a large volume of distribution, which is greatest in preterm infants and declines with maturity to adult levels by about 1 year of age.

    “Paracetamol is widely distributed in the body throughout the majority of body fluids and has a relatively large volume of distribution, which is largest in the preterm infant and reduces with maturity until it reaches adult levels at about 1 year.3”

    From Paracetamol: pharmacology, prescribing and controversies (2016) · cites this paper as [3]

    The Discussion reports that acetaminophen distributes throughout tissues and fluids, and that its volume of distribution falls from 109.7 l/70 kg at 28 weeks after conception to 72.9 l/70 kg by 60 weeks. The paper does not establish that volume of distribution reaches adult levels at about one year; its statement about reaching adult-like rates by 12 months concerns clearance (Methods). (LLM, conf=0.86)

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Research works printed but not linked: 20

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Authors
Anderson, B. J., van Lingen, R. A., Hansen, T. G., Lin, Y.-C., & Holford, N. H. G.
Affiliations
  • University of Auckland (NZ)
  • Neonatologist, Isala Clinics. ‡Anesthetist, Royal Hospital for Sick Children.
ORCID
Venue
Anesthesiology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2002-06-01
Volume
96
Issue
6
Pages
1336-1345
ISSN
0003-3022 (ISSN-L)
DOI
10.1097/00000542-200206000-00012
OpenAlex
W2162213916
Cited by
240
References
21
Citations by year
2025: 7 · 2024: 7 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 16 · 2018: 8 · 2017: 7 · 2016: 8 · 2015: 12 · 2014: 21 · 2013: 13 · 2012: 14
FWCI
5.65
Type
journal article
Language
en
Open access
Locations
  • Anesthesiology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
Keywords
paracetamol, developmental pharmacokinetics, preterm infants, infants, population pharmacokinetics, age-appropriate dosing, volume of distribution, clearance, absorption lag time, bioavailability, rectal suppositories, allometric scaling, postnatal age, pediatric analgesia
MeSH terms
Absorption, Acetaminophen, Age Factors, Biological Availability, Humans, Infant, Infant, Newborn, Infant, Premature, Metabolic Clearance Rate, Analgesics, Non-Narcotic

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