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CLINICAL INVESTIGATION

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

1
The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, 2Stanford University School of Medicine, Stanford,
California, 3Cadence Pharmaceuticals Inc, San Diego, California, 4Pharsight, a Certarae Company, Montreal, Canada

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.

INDEX TERMS acetaminophen, intravenous, pediatrics, pharmacokinetics

J Pediatr Pharmacol Ther 2011;16(4):246–261

INTRODUCTION istration (FDA) in November 2010 for the treat-

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 (para-
cetamol) 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 Admin-
ment of acute pain and fever in children (ages 2
years and older) and adults.
Outside the United States, intravenous acet-
aminophen 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)

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Pharmacokinetic Analysis of Intravenous Acetaminophen
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 con-
verted by plasma esterases to acetaminophen and
diethylglycine, and it was used for more than 20
years before the introduction of intravenous acet-
aminophen. Doses of 30 mg/kg intravenous prop-
acetamol 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 acetamin-
ophen, 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 request-
ed 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 acetamin-
ophen repeated-dose PK study and population PK
modeling analysis that includes patients across the
entire pediatric age strata.
MATERIALS AND METHODS
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 Prac-
tice guidelines. The study was conducted in
compliance with the protocol, the International
Conference on Harmonization Good Clinical Prac-
tice 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 (www.clinicaltrials.gov 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
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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, partici-
pants 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 prespeci-
fied 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 require-
ments 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 acet-
aminophen-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, german-
der, 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
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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 ¼ 11-12), infants (n ¼ 15-16), and
children/adolescents (n ¼ 18 or 20) immediately
prior to the start of the intravenous infusion, at
various timepoints during the infusion, and imme-
diately 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 me-
tabolites. The following analytes were assessed in
urine samples: acetaminophen, acetaminophen glu-
curonide, acetaminophen sulfate, 3 0 –methoxyaceta-
minophen, and N-acetyl-p-benzoquinone imine
(NAPQI)-glutathione metabolites [3 0 –(S– cystein-
yl)] acetaminophen, acetaminophen mercapturate,
and 3 0 –S–methyl-acetaminophen).
Drug Quantification
The concentrations of plasma and urine acet-
aminophen as well as urine acetaminophen metab-
olites were measured (MedTox Laboratories, St
Paul, MN) using validated methods. Acetamino-
phen 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 vari-
ous 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
615% of the diluted controls.
The assay standard curve ranges for the urine
analytes were: acetaminophen (0.05-5 mg/L), acet-
aminophen sulfate (0.25-10 mg/L), acetaminophen
glucuronide (0.25-10 mg/L), 3 0 -methoxy-acetamin-
ophen (0.1-5 mg/L), 3 0 -cysteinylacetaminophen
(0.25-5 mg/L), acetaminophen mercapturate (0.10-
5 mg/mL), and methylthioacetaminophen (0.1-5
mg/L).
248 J Pediatr Pharmacol Ther 2011 Vol. 16 No. 4  www.jppt.org
AF Zuppa, et al
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 (kz), and terminal elimination half-life
(T1/2b).
Nonlinear Mixed-Effects PK Modeling
Data set preparation, exploration, and visuali-
zation 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 (NON-
MEM; 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 combina-
tion. 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 parame-
terized by clearance (CL [L/hr]), intercompartmen-
tal 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
Pharmacokinetic Analysis of Intravenous Acetaminophen
residuals), the value of the minimum objective
function (MOF), the precision of parameter esti-
mates, 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 ¼ hTV *
(WTi / 70)hallometric, in which TV is the typical value
of a model parameter, described as a function of
individual body weight, hTV 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 hallometric is an allometric
power parameter based on physiologic consider-
ation 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 sourc-
es of variability in PK parameters of acetamino-
phen 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 popula-
tion 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 signifi-
cance, 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 equa-
tion as proposed by van der Marel et al9:
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Xj ¼ hX ðWTi =70Þhallometric
age
ð1 þ hX expðPNAj lnð2Þ=Tx ÞÞ
in which Xj is the typical parameter value for the
group of participants having the same covariate
values (WT and PNA), hX is the population
mean parameter value for the reference weight of
70 kg at mature age, hXage 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-s
(mg*hr/L), T1/2a (distribution half-life [hr]), and T1/
2b (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 metab-
olites, 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 observa-
tions were available for each age strata and
regimen.
Safety Endpoints
Safety endpoints included spontaneously report-
ed or observed AEs, clinical laboratory testing
(protocol-specified standard urine and blood tests,
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Table 1. Patient Demographics

No. (%) of No. (%) of No. (%) of No. (%) of
Neonates (n¼3)* Infants (n¼25)† Children (n¼25)‡ Adolescents (n¼22)§

Sex

Male 1 (33) 14 (56) 15 (60) 14 (64)

Female 2 (66) 11 (44) 10 (40) 8 (36)

Ethnicity

Hispanic or Latino 0 (0) 5 (20) 3 (12) 2 (9)

Not Hispanic or Latino 3 (100) 20 (80) 22 (88) 20 (91)

Race

Asian 0 (0) 3 (12) 1 (4) 1 (4)

Black or African American 1 (33) 4 (16) 1 (4) 0 (0)

Native Hawaiian/other 0 (0) 1 (4) 2 (8) 0 (0)

Pacific Islander

White or Caucasian 2 (67) 16 (64) 21 (84) 21 (96)

Other 0 (0) 1 (4) 0 (0) 0 (0)
* Full-term to 28 days
† 29 days to ,2 years
‡ 2 to ,12 years
§ 12 years

including LFTs), vital signs, physical examinations,
and urine collections to assess the production of
NAPQI/glutathione metabolites comparing frac-
tional 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 intrave-
nous acetaminophen were characterized as treat-
ment-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 clini-
cally 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 param-
eters 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 calculat-
ed. The relationships between change from baseline
in LFTs and the secondary posthoc PK parameters
(AUC0-s 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 rela-
tionship.
RESULTS
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

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Pharmacokinetic Analysis of Intravenous Acetaminophen
Figure 1. Semi-log plots of concentration vs. time for the 4 age groups.
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 neo-
nates, 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 num-
ber 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 (n¼6), failure to be admitted to intensive
care unit (n¼2), investigator preference (n¼2),
randomization error (n¼1), or lack of proper
consent (n¼1). The demographic characteristics of
the 75 participants in the PK/safety population are
represented in Table 1.
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Population PK Analysis
Concentration-time plots for neonates, infants,
children, and adolescents are presented in Figure 1.
Concentration-time profiles of acetaminophen de-
clined in a biexponential manner.
PK Model
The base model of acetaminophen was devel-
oped 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 covari-
ance term between CL and Vd1 as well as
constraining the correlation between Vd2 and Q
to unity. These parameters shared the same g,
where for each subject gQ ¼ ugVd2 and u is the
ratio of the standard deviations of random effects
(u ¼ xQ/xVd2).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
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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 squares regression smoothed line. Conditional weighted residuals vs. time (lower left
panel), and conditional weighted residuals vs. predicted concentrations (lower right panel) for the full covariate
model. The dashed black line (ZERO) represents the line of identity. The gray dashed line (LOESS) is the weighted
linear least squares regression smoothed line.

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Pharmacokinetic Analysis of Intravenous Acetaminophen
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.
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, creati-
nine 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 variabil-
ity (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
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weighted residuals vs. time, and conditional weight-
ed residuals vs. observed concentrations for the full
covariate model). Figure 3 demonstrates a sigmoi-
dal 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 interin-
dividual variability, with the respective standard
errors of the point estimates. Table 3 presents the
calculated estimates of CL and V1 for different
weights.
Model Validation
The VPC results confirmed that simulated con-
centrations 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 T1/2b values of acetaminophen in the 2
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Table 2. Parameter Estimates From the Full Covariate Urinary Acetaminophen and Metabolite
Acetaminophen Population Pharmacokinetic Model and Excretion
Noncompartmental Model† Mean values for free (unconjugated) acetamin-
ophen, acetaminophen glucuronide, acetaminophen
Population Model Final Model
sulfate, and glutathione conjugates for each age
Parameter Estimate SE, % group after the first and last doses are represented
in Table 5. Glucuronidation and sulfation repre-
CL, L/hr 18.4 4.9 sented the primary clearance pathways across the
age groups. In younger age strata, sulfation
Vd1, L 16.0 8.9
predominated over glucuronidation. Free acetamin-
Q, L/hr 97.8 7.1 ophen and production of NAPQI/glutathione
conjugates and 3-methoxy acetaminophen repre-
Vd2, L 59.5 7.1 sented minor elimination pathways.
Glutathione conjugates excreted in urine provide
PNA effect, CL 0.678 5.8
an indirect measurement of NAPQI production.
Maturation half-life, wk 41.0 52.0 Individual values of NAPQI/glutathione conjugates
after the first dose and at steady state (after the last
Parameter Individual SE, % dose day 2) were very low and appeared to be
Variability similar across the age strata.
x2CL 0.14 41.6
Safety
x2Vd1 0.38 34.2 Most (93%) of the TEAEs were assessed by
investigators to be mild or moderate in severity
x2Q 0.0383 58.5 (Table 6). No clinically relevant differences between
Ratio of x2Q/x2Vd2 2.03 37.1
age or treatment groups in the frequency of serious,
severe, related, or overall TEAEs were observed.
x2Vd2 0.0777 69.3 There were no serious TEAEs related to study
medication and no deaths reported within the 30-
Residual Variability Estimate SE, % day follow-up after the last intravenous acetamin-
ophen dose. Table 7 presents the frequent (5% in
r2proportional, % 27.9 16.8
any age group) spontaneously reported or observed
r2additive, mg/L 168.2 44.9 TEAEs. The Medical Dictionary for Regulatory
Authorities preferred terms listed are typical in a
CL, clearance; PNA, postnatal age; Q, intercompartmental
clearance; T1/2a, distribution half-life; T1/2b, terminal elimination
postoperative context.
half-life; Vd, volume of distribution; Vd1, central volume of Although there were 4 severe TEAEs, none were
distribution; Vd2, peripheral volume of distribution deemed by the investigators to be related to
† Correlation between x2CL and x2V2 was 0.546 intravenous acetaminophen. Only one hepatic TEAE
x2CL shrinkage (%): 2.5 (nonserious and mild) occurred: an adolescent male
x2V1 shrinkage (%): 19.8
who had undergone an extensive spinal fusion for
x2Q shrinkage (%): 16.5
Epsilon shrinkage (%): 6.5 scoliosis experienced an isolated aspartate amino-
x2V2 was the product of x2Q and ratio of x2Q/x2V2 and its SE was transferase elevation with normal alanine amino-
calculated using the delta method transferase, total bilirubin, and alkaline phosphatase
CL ¼ hCL * (WT/70)0.75*(10.678 *exp [PNAj * ln(2)/41]) after the surgery. Table 8 demonstrates that except
Vd1 ¼ hV1 * (WT/70)1 for aspartate aminotransferase, a nonspecific marker
Q ¼ hQ * (WT/70)0.75
Vd2 ¼ hV2 * (WT/70)1
for hepatic injury, which commonly increases after
Noncompartmental: T1/2a for a 70-kg adult ¼ 5 minutes; T1/2b for muscle trauma, it was just as likely for the LFT value
a 70-kg adult ¼ 3.2 hours to start above ULNR and normalize while on
intravenous acetaminophen treatment as it was to
become elevated during treatment.
neonates (3.9 hours) were considerably longer than
those observed in infants (2.4 hours), resulting in DISCUSSION
higher median AUC0-s values for those receiving
12.5 mg/kg per dose. Median values in Cmax from PK Modeling
children to adolescents for a given intravenous As previously noted, the 2005 population PK
acetaminophen dose were similar, whereas values in analysis of intravenous acetaminophen by Ander-
infants were slightly lower. son et al.2 included data from 7 separate PK studies

254 J Pediatr Pharmacol Ther 2011 Vol. 16 No. 4  www.jppt.org

Pharmacokinetic Analysis of Intravenous Acetaminophen JPPT
Table 3. Calculated Estimates of Clearance and Central Volume of Distribution for Different Weights
Age Weight* (kg) CL (L/hr) CL (L/hr/kg) Vd1 (L) Vd1 (L/kg)

1 month 3.68 2.02 0.55 0.84 0.23

2 months 4.71 2.43 0.52 1.1 0.23

6 months 6.40 3.06 0.48 1.5 0.23

9 months 8.26 3.70 0.45 1.9 0.23

1 year 9.43 4.09 0.43 2.2 0.23

2 years 11.31 4.69 0.41 2.6 0.23

5 years 14.80 5.74 0.39 3.4 0.23

8 years 21.74 7.65 0.35 5.0 0.23

12 years 32.73 10.40 0.32 7.5 0.23

16 years 49.86 14.27 0.29 11.4 0.23
CL, clearance; Vd, volume of distribution; Vd1, central volume of distribution; Vd2, peripheral volume of distribution
* Weights are 50th percentile for a given age and were derived from http://www.cdc.gov/growthcharts (accessed August 2011)

Table 4. Noncompartmental Pharmacokinetics Parameters of Intravenous Acetaminophen in Plasma at Steady State

(After the Last Dose Day 2)
Median (Range)
Dose Regimen and Dosing AUC0-s, T1/2b
Subpopulation Interval mg*hr/L Cmax, mg/L Tmax, hr Elimination, hr

12.5 mg/kg

Neonates (n¼2)* q 6 hr 65.6 (55.8-75.4) 19.9 (19.3-20.5) 0.46 (0.33-0.58) 3.9 (NC)

Infants (n¼13)† q 4 hr 43.3 (9.2-79.2) 21.9 (4.2-25.3) 0.29 (0.3-1.4) 2.4 (1.2-2.8)

Children (n¼9)‡ q 4 hr 37.8 (11.3-52.3) 24.3 (3.84-35.1) 0.18 (0-0.28) 2.6 (2.2-4.5)

Adolescents (n¼12)§ q 4 hr 47.7 (22.4-132) 23.9 (14.6-108) 0.33 (0-0.4) 3.4 (2.7-4.2)

15 mg/kg

Neonates (n¼1)* q 8 hr 105 (NC) 32.2 (NC) 0.25 (NC) NA

Infants (n¼12)† q 6 hr 51.9 (36-200) 20.1 (15-151) 0.25 (0-0.47) 2.8 (2.1-5.4)

Children (n¼16)‡ q 6 hr 48 (32.2-131) 25.3 (11.5-97.1) 0.27 (0.08-0.75) 2.8 (2.2-4.9)

Adolescents (n¼10)§ q 6 hr 64 (33.2-84.1) 27.1 (16.7-38.2) 0.25 (0.25-0.28) 4.1 (2.5-4.4)
AUC0-s, area under the plasma concentration–time curve from time zero to time t; Cmax, maximum plasma concentration; NA, not
assessable because the concentration-time profile did not exhibit a terminal log-linear phase and the pharmacokinetic parameter T½b
could not be calculated; NC, not calculated; Tmax, time of maximal plasma concentration; T1/2b, terminal elimination half-life
* Full-term to 28 days
† 29 days to ,2 years
‡ 2 to ,12 years
§ 12 years

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JPPT AF Zuppa, et al

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)
Neonates* Infants†
First Dose, Last Dose, First Dose, Last Dose,
Mean (Range) Mean (Range) Mean (Range) Mean (Range)
Analyte n¼2 n¼2 n¼23 n¼13

Acetaminophen} 0.07 (0.01-0.13) 2.6 (2.4-2.7) 3.9 (0.01-41.6) 4.7 (0.11- 25.4)

Acetaminophen-glucuronide} 0.4 (0.00-0.80) 13.7 (5.5-21.9) 7.8 (0.28-34.2) 22.8 (0.6- 73.3)

Acetaminophen-sulfate} 1.6 (0.00-3.2) 22.7 (14.6-30.8) 20.6 (0.57-109.5) 23.5 (0.47-55.5)

3-methoxy-acetaminophen} 0.00 (0.00-0.00) 0.1 (0.08-0.12) 0.03 (0.00-0.15) 0.79 (0.00- 3.4)

3-S-methyl-acetaminophen}# 0.05 (0-0.10) 1.1 (0.90-1.3) 1.1 (0.01-5.5) 4.4 (0.05-18.4)

3-cysteinyl-acetaminophen}# 0.06 (0-0.12) 2.7 (1.6-3.8) 0.99 (0.03-4.8) 7.3 (0.11- 25.5)

Acetaminophen-
mercaptopurate}# 0.09 (0-0.18) 5.8 (2.9-8.7) 1.5 (0.02-7.3) 7.6 (0.21- 26.0)
Total recovered 2.3 (0.01-4.5) 48.7 (28.0-69.4) 35.9 (0.92-187.4) 71.1 (1.6-216.1)
* Full-term to 28 days
† 29 days to ,2 years
‡ 2 to ,12 years
§ 12 years
} Urinary data are presented as percent fractional excretion for those participants who had data available for all 7 compounds
# Glutathione conjugates

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 acetamin-
ophen 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 6 SD weight of
2.9 6 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 hyperbil-
irubinemia 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 acetamino-
phen PK study, and a new data set (445 concen-
tration 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, neo-
nates given an intravenous acetaminophen dose of
10 mg/kg every 6 hours were predicted to achieve a

256 J Pediatr Pharmacol Ther 2011 Vol. 16 No. 4  www.jppt.org

Pharmacokinetic Analysis of Intravenous Acetaminophen
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.)
Children‡
First Dose, Last Dose,
Mean (Range) Mean (Range)
n¼22 n¼15
2.2 (0.51-10.1) 4.8 (0.16-19)
7.2 (1.6-23.9) 27.5 (3.92-121.6)
12.5 (2.4-31.8) 20.0 (2.0-53.1)
0.03 (0.00-0.29) 1.1 (0-5.6)
0.46 (0.04-1.3) 3 (0.05-21.9)
0.91 (0.13-4.9) 6 (0.34-34.2)
0.76 (0.09-3.2) 6.1 (0.32-29.0)
24.1 (7.1-51.7) 68.5 (9.6-273.4)
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 parame-
ters 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 T1/2b values of acetaminophen in
neonates appeared to be higher than those observed
in infants, children, and adolescents. Although the
number of neonates (n¼3) was small, the median
AUC0-s 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
J Pediatr Pharmacol Ther 2011 Vol. 16 No. 4  www.jppt.org
JPPT
Adolescents§
First Dose, Last Dose,
Mean (Range) Mean (Range)
n¼22 n¼13
3.2 (0.00-19.4) 6.4 (1.3-20.7)
13.1 (0.00-52) 36.2 (3.0-89.4)
12.5 (0.00-43.2) 29.2 (4.3-81.8)
0.06 (0-0.69) 0.68 (0.06-2.5)
0.73 (0-3.4) 4 (0.18-14.2)
1.2 (0.01-4.2) 8.3 (0.67-21.1)
1.1 (0.01-4.7) 7.9 (1.0-18.7)
31.9 (0.02-101.5) 92.6 (10.5-228.0)
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 acetamino-
phen 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%. Chil-
dren 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 6 3.8 mg/L
and Tmax of 1.4 6 0.5 hours. In the current study,
mean Cmax values were higher than 20 mg/L in each
257
JPPT
Table 6. Summary of Overall Adverse Events*
No. (%) of
Neonates (n¼3)†
TEAE 3 (100)
Severe TEAE 0 (0)
Related TEAE# 0 (0)
Severe related TEAE# 0 (0)
Hepatic TEAE 0 (0)
Severe AE** 0 (0)
Discontinued because 0 (0)
of a TEAE
AE, adverse event; TEAE, treatment-emergent AE (AEs occurring after T0)
* Participants with more than one TEAE were counted only once within each row
# Any TEAE considered certainly, possibly, or probably related to study medication
† Full-term to 28 days
‡ 29 days to ,2 years
§ 2 to ,12 years
} 12 years
# Any TEAE considered certainly, possibly, or probably related to study medication
** Severe AEs included both serious AEs (occurring prior to T0) and serious TEAEs (occurring after T0)
pediatric age stratum after intravenous acetamino-
phen 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 cyto-
chrome 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 differ-
ences, 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
258
AF Zuppa, et al
No. (%) of No. (%) of No. (%) of
Infants (n¼25)‡ Children (n¼25)§ Adolescents (n¼22)}
19 (76) 13 (52) 16 (72.7)
1 (4) 2 (8) 1 (4.5)
0 (0) 0 (0) 2 (9.1)
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 1 (4.5)
1 (4) 3 (12) 2 (9.1)
0 (0) 0 (0) 1 (4.5)
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-s and Cmax) and
percent change from baseline in markers of hepatic
function (total bilirubin, alanine aminotransferase,
aspartate aminotransferase, and alkaline phospha-
tase). 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 glucuroni-
dation or sulfation represented the primary path-
ways of acetaminophen elimination, with sulfation
predominating in younger age strata. Free acet-
aminophen excretion is a minor elimination path-
way, 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.
J Pediatr Pharmacol Ther 2011 Vol. 16 No. 4  www.jppt.org
Pharmacokinetic Analysis of Intravenous Acetaminophen JPPT
Table 7. Frequent (5% in Any Age Stratum) Treatment-Emergent Adverse Events
No. (%) of No. (%) of No. (%) of No. (%) of No. (%) of Total
System Organ Class Neonates Infants Children Adolescents Participants
Preferred Term* (n¼3)† (n¼25)‡ (n¼25)§ (n¼22)} (N¼75)

Blood and lymphatic system disorders

Anemia 0 (0) 2 (8) 0 (0) 0 (0) 2 (2.7)

Gastrointestinal disorders

Constipation 0 (0) 2 (8) 1 (4) 2 (9.1) 5 (6.7)

Nausea 0 (0) 1 (4) 4 (16) 7 (31.8) 12 (16.0)

Vomiting 0 (0) 0 (0) 0 (0) 2 (9.1) 2 (2.7)

General disorders and administration site conditions

Face edema 0 (0) 0 (0) 2 (8) 1 (4.5) 3 (4)

Pyrexia 0 (0) 0 (0) 1 (4) 2 (9.1) 3 (4)

Metabolism and nutrition disorders

Hypokalemia 0 (0) 3 (12) 3 (12) 1 (4.5) 7 (9.3)

Hypomagnesemia 1 (33.3) 4 (16) 1 (4) 2 (9.1) 8 (10.7)

Hypophosphatemia 0 (0) 0 (0) 2 (8) 0 (0) 2 (2.7)

Psychiatric disorders

Agitation 0 (0) 1 (4) 0 (0) 2 (9.1) 3 (4)

Respiratory/thoracic/mediastinal disorders

Atelectasis 2 (66.7) 3 (12) 3 (12) 1 (4.5) 9 (12)

Pleural effusion 1 (33.3) 4 (16) 3 (12) 2 (9.1) 10 (13.3)

Pulmonary edema 1 (33.3) 3 (12) 1 (4) 0 (0) 5 (6.7)

Stridor 0 (0) 3 (12) 0 (0) 0 (0) 3 (4)

Wheezing 0 (0) 4 (16) 0 (0) 0 (0) 4 (5.3)

Skin and subcutaneous tissue disorders

Periorbital edema 0 (0) 0 (0) 2 (8) 1 (4.5) 3 (4)

Pruritus 0 (0) 2 (8) 5 (20) 3 (13.6) 10 (13.3)
* At each level of summarization (Medical Dictionary for Regulatory Authorities system organ class or preferred term), participants who
had more than one adverse event were counted only once
† Full-term to 28 days
‡ 29 days to ,2 years
§ 2 to ,12 years
} 12 years

CONCLUSIONS patients who cannot tolerate or are not candidates

for the oral or rectal route of administration. The
Intravenous acetaminophen offers a new thera- intravenous route for acetaminophen administra-
peutic option for treating pain and fever in pediatric tion produces reliable and predictable plasma

J Pediatr Pharmacol Ther 2011 Vol. 16 No. 4  www.jppt.org 259

JPPT AF Zuppa, et al

Table 8. Changes in Quantitative Liver Function Test Values From Baseline to 48 Hours*
No. (%) of No. (%) of No. (%) of No. (%) of No. (%) of Total
Neonates Infants Children Adolescents Participants
Liver Function Test (n¼3)† (n¼25)‡ (n¼25)§ (n¼22)} (N¼75)

ALT

.ULNR to normal 0 (0) 2 (8) 1 (4) 0 (0) 3 (4)

Normal to .ULNR 0 (0) 0 (0) 1 (4) 0 (0) 1 (1.3)

AST

.ULNR to normal 0 (0) 4 (16) 4 (16) 1 (4.5) 9 (12)

Normal to .ULNR 1 (33.3) 4 (16) 4 (16) 5 (22.7) 14 (18.7)

Alkaline Phosphatase

.ULNR to normal 0 (0) 6 (24) 7 (28) 7 (31.8) 20 (26.7)

Normal to .ULNR 0 (0) 3 (12) 0 (0) 0 (0) 3 (4)

Total Bilirubin

.ULNR to normal 0 (0) 2 (8) 1 (4) 0 (0) 3 (4)

Normal to .ULNR 0 (0) 1 (4) 1 (4) 0 (0) 2 (2.7)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULNR, upper limit of normal range
* Percentages are based upon the total number of participants for each age strata
† Full-term to 28 days
‡ 29 days to ,2 years
§ 2 to ,12 years
} 12 years

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 acetamin-
ophen, and may result in more rational dosing of
intravenous acetaminophen in pediatric popula-
tions.
DISCLOSURES Drs Zuppa and Barrett declare no
conflicts or financial interest in any product or service
mentioned in the manuscript, including grants, equip-
ment, 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 stock-
holder of Cadence Pharmaceuticals.
ACKNOWLEDGEMENTS 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. Pharma-
cokinetics of IV acetaminophen in pediatric popula-
tions. Presented at the 110th Annual Meeting of the
American Society for Clinical Pharmacology and Ther-
apeutics; 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.
ABBREVIATIONS AEs, adverse events; AUC0-s, area
under the plasma concentration–time curve from time
zero to time t; CL, clearance; Cmax, maximum plasma
concentration; FDA, Food and Drug Administration; LFT,
liver function test; MOF, minimum objective function;
NAPQI, N-acetyl-p-benzoquinone imine; PK, pharma-
cokinetic; PNA, postnatal age; Q, intercompartmental
clearance; TEAEs, treatment-emergent AEs; Tmax, time
of maximal plasma concentration; TV, typical value; T1/
2a, distribution half-life; T1/2b, terminal elimination half-
life; Vd, volume of distribution; Vd1, central volume of
distribution; Vd2, peripheral volume of distribution;
VPC, visual predictive check; WT, weight in model

260 J Pediatr Pharmacol Ther 2011 Vol. 16 No. 4  www.jppt.org

Pharmacokinetic Analysis of Intravenous Acetaminophen
CORRESPONDENCE Athena F. Zuppa, MD, MSCE,
The Children’s Hospital of Philadelphia, Colket Transla-
tional Research Building, Room 4012, 34th Street and
Civic Center Blvd, Philadelphia, PA 19104-4318 email:
ZUPPA@email.chop.edu
Ó 2011 Pediatric Pharmacy Advocacy Group
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