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J Pediatr Pharmacol Ther. 2011 Oct-Dec; 16(4): 246–261.
PMCID: PMC3385039

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

Athena F. Zuppa, MD, MSCE,1 Gregory B. Hammer, MD,2 Jeffrey S. Barrett, PhD,1 Brian F. Kenney, BS,3 Nastya Kassir, PharmD,4 Samer Mouksassi, PharmD,4 and Mike A. Royal, MD, JD, MBA3



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.


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.


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.


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.

INDEX TERMS: acetaminophen, intravenous, pediatrics, pharmacokinetics


Acetaminophen has been recognized as an analgesic for more than a century, and its oral form has been used for pain relief and antipyresis in the United States since 1955. In 2002, a stable formulation of intravenous acetaminophen (paracetamol) was first commercialized in Europe and marketed as Perfalgan (Bristol-Myers Squibb, New York, NY). Acetaminophen injection (Ofirmev, Cadence Pharmaceuticals Inc, San Diego, CA) was approved by the US Food and Drug Administration (FDA) in November 2010 for the treatment of acute pain and fever in children (ages 2 years and older) and adults.

Outside the United States, intravenous acetaminophen has been widely used as an antipyretic and postoperative analgesic, both alone and in conjunction with intravenous opioids, nonsteroidal anti-inflammatory–specific and cyclooxygenase-2–specific analgesics, and with various multimodal analgesic regimens.1 Nonetheless, the published data on acetaminophen pharmacokinetic (PK) parameters in pediatric populations after repeated-dose intravenous acetaminophen administration have been limited. For example, although the 2005 population PK analysis2 of intravenous acetaminophen included data from 7 separate PK studies, all 7 used intravenous propacetamol, a prodrug of acetaminophen. Propacetamol is converted by plasma esterases to acetaminophen and diethylglycine, and it was used for more than 20 years before the introduction of intravenous acetaminophen. Doses of 30 mg/kg intravenous propacetamol are equivalent to approximately 15 mg/kg acetaminophen. Although these products have similar PK parameters, they are not bioequivalent.

Since the recent Anderson et al2 analysis, two additional PK studies using intravenous acetaminophen, both in neonates, have been published.3-5 At the time of the FDA agreement on the US pediatric development plan for intravenous acetaminophen, no multiday pediatric safety data with intravenous acetaminophen existed; therefore, the FDA requested that a 5-day safety study and 48-hour safety and PK study that included an assessment of urine acetaminophen metabolites be performed. As a direct result, this is the first intravenous acetaminophen repeated-dose PK study and population PK modeling analysis that includes patients across the entire pediatric age strata.


Study Conduct and Design

The protocol and the informed consent form were approved by an institutional review board operating in compliance with current regulations of local regulatory authorities and the International Conference on Harmonization Good Clinical Practice guidelines. The study was conducted in compliance with the protocol, the International Conference on Harmonization Good Clinical Practice guidelines, and Title 21 of the US Code of Federal Regulations Parts 50 (protection of human subjects), 56 (institutional review boards), and 312 (investigational new drug application).

This was a phase 1, multicenter, randomized, open-label study with the primary objectives of describing the PK and safety of repeated doses of intravenous acetaminophen during 48 hours across all pediatric age strata ( study identifier: NCT00493246). A minimum of 12 neonates, 18 infants, 12 children, and 12 adolescents with evaluable PK data were to be enrolled. In response to the delay in neonate enrollment, the protocol was amended to require no minimum enrollment for this age group. Over-enrollment in each age stratum was allowed until it was confirmed that each dosing group within an age stratum was filled.

After written informed consent was obtained from the parent or guardian (with participant assent, when appropriate), screening assessments were performed. If eligible for the study, participants were then randomized to one of two dosing regimens within each age strata (see dosing section below). During the treatment period (T0 to T48 hours), the following were performed at prespecified time points: liver function tests (LFTs), PK samples, urinary collection, vital signs, recording of spontaneously reported or observed adverse drug events (ADEs) (from the time of consent/assent to study completion), and concomitant medications.

Study Population

Full-term neonates (full-term to 28 days), infants (29 days to <2 years), children (2 to <12 years), and adolescents (≥12 years) with normal hepatic and renal functions who required analgesic or antipyretic therapy were eligible for enrollment. All eligible participants were hospitalized during the study period and were required to have intravenous access for the duration of the study. Participants were not eligible for study participation if they were unable to comply with the blood sampling requirements of the study, had a known hypersensitivity to acetaminophen or the inactive excipients of the formulation, had impaired liver function (total bilirubin more than 1.5 times the upper limit of the normal range [ULNR] for age or an alanine aminotransferase or aspartate aminotransferase more than 2.5 times ULNR), had renal function calculated to be less than 33% of normal for the applicable age strata, or had received any acetaminophen-containing products in the 12 hours prior to randomization. In addition, patients taking any of the following medications during the prior 48 hours were excluded: probenecid, disulfiram, isoniazid, or a number of dietary supplements (St John's wort, skullcap, chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, and valerian).

Dosing Regimens Selected

Neonates were randomized to receive either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours, and infants, children, and adolescents were randomized to receive either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. The maximum single dose could not exceed the lesser of 12.5 or 15 mg/kg or 1000 mg, and the maximum daily dose could not exceed the lesser of 75 mg/kg or 4000 mg. Intravenous acetaminophen was provided as a 100-mL vial containing 1000 mg (10 mg/mL). Each intravenous acetaminophen dose was delivered as a 15-minute infusion using a syringe pump.

PK Sampling (Blood and Urine)

The PK blood sampling schedule varied based on age and dosing group. Samples were obtained in neonates (n = 11-12), infants (n = 15-16), and children/adolescents (n = 18 or 20) immediately prior to the start of the intravenous infusion, at various timepoints during the infusion, and immediately at the end of infusion.

A 4-hour urine collection was performed after the first dose and a 12-hour urine collection (two aliquots: 0-4 hours and 4-12 hours) was obtained following the last dose to assess urinary excretion of free acetaminophen and key acetaminophen metabolites. The following analytes were assessed in urine samples: acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, 3′–methoxyacetaminophen, and N-acetyl-p-benzoquinone imine (NAPQI)-glutathione metabolites [3′–(S– cysteinyl)] acetaminophen, acetaminophen mercapturate, and 3′–S–methyl-acetaminophen).

Drug Quantification

The concentrations of plasma and urine acetaminophen as well as urine acetaminophen metabolites were measured (MedTox Laboratories, St Paul, MN) using validated methods. Acetaminophen in plasma was analyzed using methanol-induced protein precipitation followed by high-performance liquid chromatography–tandem mass spectrometry capable of analyzing acetaminophen over a concentration range of 0.050 to 30 mg/L using d4-acetaminophen (sourced from Cerilliant, Round Rock, TX; lot no. 33378-95B) as an internal standard. The lower limit of quantitation was 0.050 mg/L. The intra-assay precision and accuracy ranged from 0.2% to 6% and 96.8% to 102.3%, respectively. The inter-assay precision and accuracy ranged from 2.1% to 5% and 95.9% to 102.3%, respectively. When sample concentrations of various analytes were found to be greater than the validated upper limit of quantitation for the assays, dilution was performed and samples were compared with high-quality control samples. The dilution process analysis was considered acceptable if within ±15% of the diluted controls.

The assay standard curve ranges for the urine analytes were: acetaminophen (0.05-5 mg/L), acetaminophen sulfate (0.25-10 mg/L), acetaminophen glucuronide (0.25-10 mg/L), 3′-methoxy-acetaminophen (0.1-5 mg/L), 3′-cysteinylacetaminophen (0.25-5 mg/L), acetaminophen mercapturate (0.10-5 mg/mL), and methylthioacetaminophen (0.1-5 mg/L).

Statistical Analysis

Noncompartmental PK Analyses

Noncompartmental plasma acetaminophen PK analysis after the first and final doses included: area under the plasma concentration-time curve from time zero to time t (AUC0-t), maximum plasma concentration (Cmax), time of maximal plasma concentration (Tmax), terminal elimination rate constant (λz), and terminal elimination half-life (T1/2β).

Nonlinear Mixed-Effects PK Modeling

Data set preparation, exploration, and visualization of the data were performed using S-PLUS version 8.0.4 (TIBCO Software Inc, Palo Alto, CA), R version 2.6.1, and Microsoft Office Excel 2003 (Redmond, WA). The programming library Perl-Speaks-nonlinear mixed-effect modeling (NONMEM; PsN V2.3.0, ICON plc, Dublin, Ireland) was used to evaluate and validate the models with a visual predictive check (VPC). The results of the model validation were analyzed using S-PLUS version 8.0.4. WinNonlin Enterprise version v5.2 (Pharsight, A Certara Company, St. Louis, MO) was used to generate tables of posthoc PK parameters of acetaminophen as well as descriptive statistics for each treatment–age strata combination. Population PK analysis of acetaminophen in plasma was performed using nonlinear mixed-effect modeling (NONMEM) version VI. All models were run with the first-order conditional estimation with interaction method. The models accounted for between-subject variability, residual variability (random effects), as well as parameter differences predicted by covariates (fixed effects).

Base Model

A two-compartment disposition model was deemed optimal to define the acetaminophen plasma concentration profile based on results from the model-building process. Models were parameterized by clearance (CL [L/hr]), intercompartmental clearance (Q [L/hr]), central volume of distribution (Vd1 [L]), and peripheral volume of distribution (Vd2 [L]), and were explored using various inter-individual random effect covariance structures. Additive, proportional, and combined (additive and proportional) residual-error models were considered during the model-building process. Ultimately, a combined additive and proportional error model was used to describe random residual variability.

The process of model discrimination was guided by examination of model diagnostic plots (plots of predicted vs. observed concentrations; weighted residuals vs. time; weighted residuals vs. predicted residuals), the value of the minimum objective function (MOF), the precision of parameter estimates, and the symmetry of the distributions of individual parameter estimates about the estimated median parameter.

The impact of weight on all PK parameters was investigated using an allometric model: TV = θTV * (WTi / 70)θallometric, in which TV is the typical value of a model parameter, described as a function of individual body weight, θTV is an estimated parameter describing the typical PK parameter value for an individual with weight equal to the reference weight represented by WTi, 70 kg is the reference weight, and θallometric is an allometric power parameter based on physiologic consideration of size impact on metabolic processes and is fixed at a value of 0.75 for clearances, and a value of 1 for volumes.3,6,7

Covariate Analysis

The following covariates were included in the population PK data set: weight (kg), postnatal age (PNA) in weeks, height (cm), body mass index (kg/m2), serum creatinine (mg/dL), and creatinine clearance (mL/min per 1.73 m2). The creatinine clearance was calculated based on the formula of Schwartz et al8 The data set included also the results of LFTs measured prior to drug administration: total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase.

Following identification of the structural PK models, the PK parameters of acetaminophen were derived by the structural model for each patient (i.e., posthoc Bayesian PK parameters). Individual Bayesian estimates were plotted against clinical and demographic covariates to identify potential sources of variability in PK parameters of acetaminophen in pediatric patients. Covariates included but were not limited to body weight, age, and sex. Potential covariates selected from the graphical analyses were sequentially tested into the population PK model to assess the effect on between-subject variability of PK parameters of interest. A decrease in the MOF of 6.63 (p<0.01) was considered significant to include the covariate in the final model. The decision to include a covariate in the final model was based on statistical significance, clinical relevance and clinical significance. Clinical significance was evaluated based on the ability of a particular covariate to explain at least 5% of the between-subject variability of the corresponding parameter.

The effect of PNA on PK parameters was evaluated using the following age-maturation equation as proposed by van der Marel et al9:

equation image

in which Xj is the typical parameter value for the group of participants having the same covariate values (WT and PNA), θX is the population mean parameter value for the reference weight of 70 kg at mature age, θXage is the constant describing age-related changes of parameter X, PNAj is the age in weeks of the participant, and Tx represents the maturation half-lives of the age-related changes of parameter X.

Model Evaluation and Validation

The appropriateness of the final model to perform simulations was evaluated using VPC on the quantiles of concentrations of acetaminophen. A total of 1000 replicates of the study were simulated with the final population PK model. The VPC examined the ability of the model to reproduce results similar to those from the original data set. A total of 1000 replicates of the study were simulated with the final population PK model. Median values as well as 25th, 75th, 90th, and 95th percentiles of the simulated data for acetaminophen exposure metrics were plotted with the actual study data overlaid. The appropriateness of the model was assessed by the ability of the simulations to accurately describe the distribution of the actual study data.

Determination of Secondary PK Endpoints

The following secondary PK endpoints were derived in the PK analysis: Cmax (mg/L), AUC0-τ (mg*hr/L), T1/2α (distribution half-life [hr]), and T1/2β (terminal elimination half-life [hr]).

Determination of Urinary Metabolites

Urinary excretion of free acetaminophen and metabolites was evaluated using noncompartmental analysis methods. The fraction of acetaminophen recovered as the free form and as metabolites was calculated taking into account the molar weight of each analyte. Individual urine concentrations and PK parameters of free acetaminophen and metabolites, determined over the 4 hour period after the first dose and at steady-state (after the last or 8th dose), and were summarized with descriptive statistics and compared when at least two observations were available for each age strata and regimen.

Safety Endpoints

Safety endpoints included spontaneously reported or observed AEs, clinical laboratory testing (protocol-specified standard urine and blood tests, including LFTs), vital signs, physical examinations, and urine collections to assess the production of NAPQI/glutathione metabolites comparing fractional excretion after the first dose and at steady state (last dose day 2).

AEs were categorized based on incidence, type, expectedness, severity (i.e., mild, moderate, severe), seriousness, and relatedness. Investigators used standard definitions to determine relatedness (e.g., related, probably related, possibly related, not likely related, unrelated), presence of a serious AE, and level of severity (mild, moderate, severe). AEs occurring during or after the first dose of intravenous acetaminophen were characterized as treatment-emergent AEs (TEAEs). Preexisting AEs (prior to T0) that worsened during or after the first dose were also considered to be TEAEs. The percentage of participants withdrawn because of AEs and the percentage of participants with serious AEs were determined. Serious AEs included both serious AEs (occurring prior to T0) and serious TEAEs (occurring after T0).

Investigators determined the presence of clinically meaningful changes from baseline laboratory parameters (protocol-specified standard urine and blood tests); systolic blood pressure, diastolic blood pressure, and heart rate values immediately before and after the first intravenous study medication dosing, and at study completion/early termination; and change from the T0 predose value to after first dose, and final measurement.

The relationship between individual PK parameters and LFTs was evaluated to assess the safety of acetaminophen treatment in pediatric patients. Relative changes from baseline of LFTs between the screening and end-of-study visits were calculated. The relationships between change from baseline in LFTs and the secondary posthoc PK parameters (AUC0-τ and Cmax) were evaluated to assess the safety of acetaminophen treatment in the pediatric population. Pearson correlation coefficients (r) were calculated to identify significant linear relationship.


Study Conduct and Participant Disposition

This study was conducted at 5 sites within the United States from June 2007 to September 2008. Participants who received at least one dose of intravenous acetaminophen and had at least one PK sampling assessment performed were included in the final PK analysis. The minimum number of participants per age strata was achieved. Of the 81 participants randomized, 75 participants (3 neonates, 25 infants, 25 children, and 22 adolescents) received intravenous acetaminophen and were included in the PK analysis. Each of these 75 participants received at least one full dose of intravenous acetaminophen (regardless of the number of PK assessments) and was included in the safety population. Because all 75 participants also had PK assessments, the safety population is identical to the PK analysis population.

A total of 5 infants, 8 children, and 6 adolescents did not complete the 48-hour study period. One child and one adolescent terminated prematurely as a result of an AE; one infant, one child, and three adolescents withdrew consent/assent. Other reasons for premature discontinuation included loss of the intravenous line or inability to access blood for PK analyses (n=6), failure to be admitted to intensive care unit (n=2), investigator preference (n=2), randomization error (n=1), or lack of proper consent (n=1). The demographic characteristics of the 75 participants in the PK/safety population are represented in Table 1.

Table 1.
Patient Demographics

Population PK Analysis

Concentration-time plots for neonates, infants, children, and adolescents are presented in Figure 1. Concentration-time profiles of acetaminophen declined in a biexponential manner.

Figure 1.
Semi-log plots of concentration vs. time for the 4 age groups.

PK Model

The base model of acetaminophen was developed using a data set including 1094 concentration values from the 75 pediatric participants. A two-compartment model with linear elimination and weight effects on CL, Q, Vd1, and Vd2 resulted in a statistically significant decrease in MOF relative to one-compartment models and markedly improved the quality of fit. This model was refined by optimizing random-effect matrices with a covariance term between CL and Vd1 as well as constraining the correlation between Vd2 and Q to unity. These parameters shared the same η, where for each subject ηQ = [var phi]·ηVd2 and [var phi] is the ratio of the standard deviations of random effects ([var phi] = ωQVd2).10 This approach improved the stability of the population PK model by reducing the complexity of the variance-covariance matrix of the between-subject variability. This final base model provided the best quality of fit and the lowest MOF. The allometric model included power exponents of 0.75 for clearances (CL and Q) and 1 for volumes (Vd1 and Vd2).

Covariate Analysis

Small positive trends were observed between the random effects for CL and creatinine clearance, weight, height, and PNA. Although weight was included in the base PK model, a residual trend was observed between CL and PNA as well as other factors naturally correlating with PNA (ie, creatinine clearance, weight and height). Based on these results, the statistical significance of PNA on CL was evaluated in the covariate analysis. During the first step, the inclusion of PNA with a maturation function on CL resulted in a marked decrease in MOF (45 points) and explained a significant portion of the between-subject variability of CL (from 48.2% to 37.4%). Although the effect of sex on CL resulted in a statistically significant decrease in MOF (−7.01), this covariate did not explain a significant portion of the between-subject variability (with a marginal reduction of only 0.8%). As a result, sex was not retained as a covariate in the population PK model.

There was no systematic bias in the estimation of plasma concentrations for the entire study, as shown in Figure 2 (plots of the observed vs. population predicted concentrations, observed vs. individual predicted concentrations, conditional weighted residuals vs. time, and conditional weighted residuals vs. observed concentrations for the full covariate model). Figure 3 demonstrates a sigmoidal pattern between CL and PNA with a plateau of 18.4 L/hr per 70 kg in children and adolescents (ages between 2 and 12 years), and inidicates that normalized CL in children older than 2 years is similar to that in adolescents and adults. For those younger than 2 years, CL is reduced as a result of well-understood maturational changes. Table 2 presents the final parameter estimates and interindividual variability, with the respective standard errors of the point estimates. Table 3 presents the calculated estimates of CL and V1 for different weights.

Figure 2.
Plot of the observed vs. predicted concentrations (upper left panel), observed vs. individual predicted concentrations (upper right panel). The dashed black line (Ident) is the line of identity. The gray dashed line (LOESS) is a weighted linear least ...
Figure 3.
The relationship between clearance and postnatal age: a sigmoidal pattern with a clearance plateau of 18.4 L/hr per 70 kg observed in children and adolescents.
Table 2.
Parameter Estimates From the Full Covariate Acetaminophen Population Pharmacokinetic Model and Noncompartmental Model†
Table 3.
Calculated Estimates of Clearance and Central Volume of Distribution for Different Weights

Model Validation

The VPC results confirmed that simulated concentrations were consistent with the observed data in pediatric patients for all treatment groups. Most of observed concentrations were within the 75th quantile interval of the predicted concentrations.

Secondary PK Parameters

Table 4 presents the noncompartmental PK parameters for intravenous acetaminophen at steady state. Although the sample size for neonates was quite small, for the 12.5 mg/kg per dose group, the median T1/2β values of acetaminophen in the 2 neonates (3.9 hours) were considerably longer than those observed in infants (2.4 hours), resulting in higher median AUC0-τ values for those receiving 12.5 mg/kg per dose. Median values in Cmax from children to adolescents for a given intravenous acetaminophen dose were similar, whereas values in infants were slightly lower.

Table 4.
Noncompartmental Pharmacokinetics Parameters of Intravenous Acetaminophen in Plasma at Steady State (After the Last Dose Day 2)

Urinary Acetaminophen and Metabolite Excretion

Mean values for free (unconjugated) acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, and glutathione conjugates for each age group after the first and last doses are represented in Table 5. Glucuronidation and sulfation represented the primary clearance pathways across the age groups. In younger age strata, sulfation predominated over glucuronidation. Free acetaminophen and production of NAPQI/glutathione conjugates and 3-methoxy acetaminophen represented minor elimination pathways.

Table 5.
Urinary Excretion Over 4 Hours of Free Acetaminophen and Acetaminophen Metabolites After the First Dose (Day 1) and at Steady State (Last Dose, Day 2)

Glutathione conjugates excreted in urine provide an indirect measurement of NAPQI production. Individual values of NAPQI/glutathione conjugates after the first dose and at steady state (after the last dose day 2) were very low and appeared to be similar across the age strata.


Most (93%) of the TEAEs were assessed by investigators to be mild or moderate in severity (Table 6). No clinically relevant differences between age or treatment groups in the frequency of serious, severe, related, or overall TEAEs were observed. There were no serious TEAEs related to study medication and no deaths reported within the 30-day follow-up after the last intravenous acetaminophen dose. Table 7 presents the frequent (≥5% in any age group) spontaneously reported or observed TEAEs. The Medical Dictionary for Regulatory Authorities preferred terms listed are typical in a postoperative context.

Table 6.
Summary of Overall Adverse Events*
Table 7.
Frequent (≥5% in Any Age Stratum) Treatment-Emergent Adverse Events

Although there were 4 severe TEAEs, none were deemed by the investigators to be related to intravenous acetaminophen. Only one hepatic TEAE (nonserious and mild) occurred: an adolescent male who had undergone an extensive spinal fusion for scoliosis experienced an isolated aspartate aminotransferase elevation with normal alanine aminotransferase, total bilirubin, and alkaline phosphatase after the surgery. Table 8 demonstrates that except for aspartate aminotransferase, a nonspecific marker for hepatic injury, which commonly increases after muscle trauma, it was just as likely for the LFT value to start above ULNR and normalize while on intravenous acetaminophen treatment as it was to become elevated during treatment.

Table 8.
Changes in Quantitative Liver Function Test Values From Baseline to 48 Hours*


PK Modeling

As previously noted, the 2005 population PK analysis of intravenous acetaminophen by Anderson et al.2 included data from 7 separate PK studies that used intravenous propacetamol, a prodrug of acetaminophen, and included a total of 846 concentrations from 144 children (ages 27 weeks to 14 years). The current data set included 1094 concentration values in 75 children, a richer sampling scheme that resulted from reduced sample volume requirements due to analytic method improvements. In the Anderson et al2 PK analysis, normalized CL values reached 84% of mature values by 1 year of age and appeared to plateau at a value similar to that calculated in the current analysis. The authors noted that a mean acetaminophen plasma concentration of 10 mg/L can be achieved in children 2 years and older when given intravenous propacetamol 30 mg/kg, a dose roughly equivalent to intravenous acetaminophen 15 mg/kg.

Palmer et al3 studied intravenous acetaminophen PK in 50 newborn infants (43 neonates and 7 infants) with a mean (range) postmenstrual age of 38.6 weeks (32-45 weeks) and mean ± SD weight of 2.9 ± 0.7 kg who received a mean of 15 doses over a median of 4 days. This data set included 189 acetaminophen concentration values and 231 LFT measurements. The authors noted that standardized population parameter estimates for a term neonate were a CL of 5.24 L/hr per 70 kg and a Vd of 76 L/70 kg, with the presence of unconjugated hyperbilirubinemia being associated with reduced CL. Acetaminophen concentrations exceeding 10 mg/L at steady state were predicted after 15 mg/kg every 6 hours for a full-term neonate. Analysis of LFT values showed that 1 of 50 newborns (37 weeks postmenstrual age at birth; 18 days postnatal age; 2 kg male) had alanine aminotransferase values increase from 45 IU/L before surgery to 174 IU/L 2 days after pyeloplasty for severe hydronephrosis after 5 doses of intravenous acetaminophen, and values decreased to 97 IU/L by discharge 2 days later.

In the most recently published PK analysis, Allegaert et al4 performed an analysis of 943 acetaminophen concentrations from 158 neonates (including 21 extreme preterm neonates, with 19 having a birth weight less than 1.5 kg). They included data from two prior propacetamol PK studies: the Palmer et al3 intravenous acetaminophen PK study, and a new data set (445 concentration values in 60 neonates) from an intravenous acetaminophen PK study performed by Allegaert et al4 The authors noted that body weight as used to predict patient size was the major covariate of CL variance in neonates. Using their estimates, neonates given an intravenous acetaminophen dose of 10 mg/kg every 6 hours were predicted to achieve a mean acetaminophen plasma concentration of 11 mg/L. The authors also noted that as a result of the increased Vd in neonates, a loading dose of 20 mg/kg was recommended.

In the current study the PK and safety of repeated-dose intravenous acetaminophen were assessed over a 48-hour period across all pediatric age strata. The final population PK model with allometric scaling components on all PK parameters as well as a maturation function on CL fit the data well. A sigmoidal pattern between normalized CL of acetaminophen and PNA was observed, with a CL plateau of 18.4 L/hr per 70 kg observed at approximately 2 years of age, suggesting that children and adolescents would display a CL value similar to adults. These results are consistent with previously reported analyses after intravenous propacetamol.2 Median Cmax values appeared to be similar across dose concentrations and age groups, although the neonate results are limited by the small numbers enrolled.

Consistent with previous observations from Arana et al11 the T1/2β values of acetaminophen in neonates appeared to be higher than those observed in infants, children, and adolescents. Although the number of neonates (n=3) was small, the median AUC0-τ values were 60% to 90% higher than those observed in children and adolescents. Assuming that PK parameters of acetaminophen in children/adolescents were representative of those from an adult population, full-term neonate patients likely would require a dose adjustment as shown by Palmer et al3 and Allegaert et al.4

PK/Pharmacodynamic (Acute Pain) Correlation

Anderson et al12 were the first to demonstrate the correlation between acetaminophen plasma concentration and pain response in a prospective, randomized, double-blind study of 100 children (ages 3-15 years) who underwent an elective tonsillectomy with or without adenoidectomy and received either 40 mg/kg oral or rectal acetaminophen 40 minutes prior to the surgery. Children given oral acetaminophen had a higher mean acetaminophen concentration approximately 1 hour after dosing compared with rectal dosing (22.7 vs. 7.6 mg/L, respectively). The authors noted that variable and erratic rectal absorption accounts for this significant difference. The use of rescue morphine was higher in the rectal (23 of 50) vs. the oral (10 of 50) group (p<0.001). The rectal group described unsatisfactory analgesia in 46%. Children with acetaminophen concentrations higher than 10 mg/L had superior analgesic response compared with those with values below this concentration (p<0.05). For example, at 10 mg/L, 25% (16 of 62) of children failed to achieve adequate analgesia, whereas at 20 mg/L, only 6% failed to do so.

Note that in Rømsing et al13 an oral dose of 22.5 mg/kg produced a mean Cmax of 12.7 ± 3.8 mg/L and Tmax of 1.4 ± 0.5 hours. In the current study, mean Cmax values were higher than 20 mg/L in each pediatric age stratum after intravenous acetaminophen 15 mg/kg dosing, with 100% of participants exceeding the 10 mg/L threshold value. The mean Tmax after intravenous acetaminophen occurred at the end of the 15-minute infusion. Acetaminophen by the intravenous route can produce reliable and predictable plasma concentrations that are not achieved with oral or rectal dosing.

Hepatic Safety and Urinary Metabolite Excretion

A small portion (typically less than 10%) of acetaminophen is metabolized by the cytochrome P450–catalyzed oxidative system (primarily cytochrome 2E1), forming NAPQI, a highly reactive intermediate that is responsible for hepatotoxicity when not detoxified by glutathione.14 Piñeiro-Carrerro and Piñeiro15 have noted that young children may be more resistant to acetaminophen-induced hepatotoxicity than adults as a result of increased glutathione stores and metabolism differences, whereas Tenenbein16 suggested that the relative resistance is due to the larger liver size in comparison with body size.

Only a single hepatic TEAE occurred during the study that was deemed possibly related to treatment with intravenous acetaminophen, a case in which the isolated aspartate aminotransferase elevation could be explained by the extensive muscle trauma from the multilevel spinal fusion surgery. Although quantitative LFT elevations were observed during the study, the number of participants with LFT values that started above normal range prior to treatment and normalized while on intravenous acetaminophen was similar to the number of participants with LFT values that were normal at baseline and became elevated during treatment. No trend was observed between individual exposure values of acetaminophen (AUC0-τ and Cmax) and percent change from baseline in markers of hepatic function (total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase). These results are consistent with those previous observations by Arana et al11 Palmer et al3 and a review of repeated-dose intravenous acetaminophen exposure up to 20 days in 189 neonates by Allegaert et al.17

In the current study, acetaminophen glucuronidation or sulfation represented the primary pathways of acetaminophen elimination, with sulfation predominating in younger age strata. Free acetaminophen excretion is a minor elimination pathway, and the results are consistent with findings of Miller et al18 and Levy et al19 that little (1%-4%) of the acetaminophen dose is excreted unchanged. Individual values of NAPQI/glutathione conjugates excreted in the urine after the first dose and at steady state (after the last dose day 2) were very low and appeared to be similar across the age strata.


Intravenous acetaminophen offers a new therapeutic option for treating pain and fever in pediatric patients who cannot tolerate or are not candidates for the oral or rectal route of administration. The intravenous route for acetaminophen administration produces reliable and predictable plasma concentrations exceeding the 10 mg/L threshold value previously reported to be therapeutic. These doses of intravenous acetaminophen were well tolerated across all pediatric age strata. The population PK model derived in the current study can be used to predict concentrations and exposure values of acetaminophen in different age groups receiving various regimens of intravenous acetaminophen, and may result in more rational dosing of intravenous acetaminophen in pediatric populations.


This study was funded by Cadence Pharmaceuticals Inc. These data had been presented previously: Zuppa AF, Hammer G, Malviya S, Mouksassi S, Barrett JS, Kenney B, Royal MA. Pharmacokinetics of IV acetaminophen in pediatric populations. Presented at the 110th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics; Washington, DC, March 21, 2009. Dr. Zuppa and Dr. Royal drafted an early version of the manuscript and Dr. Hammer, Dr. Barrett, Mr. Kenney, Dr. Kassir, Dr. Mouksassi made significant contributions to the manuscript.


adverse events
area under the plasma concentration–time curve from time zero to time t
maximum plasma concentration
Food and Drug Administration
liver function test
minimum objective function
N-acetyl-p-benzoquinone imine
postnatal age
intercompartmental clearance
treatment-emergent AEs
time of maximal plasma concentration
typical value
distribution half-life
terminal elimination half-life
volume of distribution
central volume of distribution
peripheral volume of distribution
visual predictive check
weight in model


DISCLOSURES Drs Zuppa and Barrett declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Dr Hammer has participated in an advisory board meeting on behalf of Cadence Pharmaceuticals. Mr Kenney is an employee of Cadence Pharmaceuticals. Drs Kassir and Mouksassi are Consultants to Cadence Pharmaceuticals. Dr Royal is an employee and stockholder of Cadence Pharmaceuticals.

Table 5.
Urinary Excretion Over 4 Hours of Free Acetaminophen and Acetaminophen Metabolites After the First Dose (Day 1) and at Steady State (Last Dose, Day 2) (ext.)


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