Safety and Population Pharmacokinetic Analysis of Intravenous Acetaminophen in Neonates, Infants, Children, and Adolescents With Pain or Fever

Abstract

OBJECTIVES The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

Pharmacogenomics of acetaminophen in pediatric populations: a moving target

“…The clearance (L/hr) of APAP increased from 2.02 L/hr at 1 month of age to 4.09 L/hr at 1 year of age to 14.27 L/hr at 16 years of age (based on our own analyses on the published mean values with a Spearman correlation, there is a significant correlation between age and APAP clearance, p < 0.0001), while the central volume of distribution remained constant at 0.23 L/kg for all ages. Also, the AUC values were 60 to 90% higher than those measured in children and adolescents in the study ( Zuppa et al, 2011 ). Although it is unclear whether this is statistically significant because of the small number of neonates in the study ( n ≤ 2), the data indicate a possibly large variability in the elimination of APAP in the pediatric population, especially between neonates and older children ( Zuppa et al, 2011 ).…”

“…Also, the AUC values were 60 to 90% higher than those measured in children and adolescents in the study ( Zuppa et al, 2011 ). Although it is unclear whether this is statistically significant because of the small number of neonates in the study ( n ≤ 2), the data indicate a possibly large variability in the elimination of APAP in the pediatric population, especially between neonates and older children ( Zuppa et al, 2011 ).…”

“…APAP metabolism and excretion processes are very complex with both Phase I (oxidation) and Phase II metabolism pathways (glucuronidation, sulfation, and glutathione conjugation) involved ( Figure 1 ). In the aforementioned study and illustrated in Figure 2 , the fraction of APAP-sulfate excreted is fairly similar across age groups, indicating that APAP sulfation is likely constant among all ages ( Zuppa et al, 2011 ). In contrast, the increased fraction of 3-cysteinyl-APAP recovered along with age suggests that there might be an increase in activity of either oxidative or glutathione S-transferase (GST) enzyme isoform activity from neonate to adolescence populations.…”

“…As has been observed with many other drugs, the variability in APAP PK varies with age from birth to adulthood. In a study performed on 75 subjects (3 neonates, 25 infants, 25 children, and 22 adolescents), a PK model was developed from data following intravenous APAP administration ( Zuppa et al, 2011 ). The clearance (L/hr) of APAP increased from 2.02 L/hr at 1 month of age to 4.09 L/hr at 1 year of age to 14.27 L/hr at 16 years of age (based on our own analyses on the published mean values with a Spearman correlation, there is a significant correlation between age and APAP clearance, p < 0.0001), while the central volume of distribution remained constant at 0.23 L/kg for all ages.…”

“…They often require vastly different treatment because of their dynamic physiology that affects the pharmacokinetics (PK), including absorption, distribution, metabolism, and excretion (ADME) of many drugs. Differences in APAP PK, pharmacodynamics (PD), toxicity profile and efficacy between individuals and populations have been widely noted ( Ward et al, 2001 ; Pineiro-Carrerro and Pineiro, 2004 ; Zuppa et al, 2011 ; Leonis et al, 2013 ). While pharmacogenetic and pharmacogenomic approaches have been applied to understand the inter-patient difference in pharmacological phenotypes of many drugs, studies in these areas addressing the variability of APAP PK/PD are still limited.…”