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Pharmacology
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Levofloxacin Pharmacokinetics in Children

Shuchean Chien, Thomas G. Wells, Jeffrey L. Blumer, Gregory L. Kearns, John S. Bradley, Joseph A. Bocchini, Jr, Jaya
Natarajan, Samuel Maldonado and Gary J. Noel
J. Clin. Pharmacol. 2005; 45; 153
DOI: 10.1177/0091270004271944

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ARTICLE
CHIEN ET AL
10.1177/0091270004271944
LEVOFLOXACIN
PEDIATRICS PHARMACOKINETICS IN CHILDREN
Levofloxacin Pharmacokinetics in Children
Shuchean Chien, MS, Thomas G. Wells, MD, Jeffrey L. Blumer, MD,
Gregory L. Kearns, PharmD, PhD, John S. Bradley, MD, Joseph A. Bocchini, Jr, MD,
Jaya Natarajan, PhD, Samuel Maldonado, MD, MPh, and Gary J. Noel, MD
Levofloxacin is a broad-spectrum fluoroquinolone antibiotic
with activity against many pathogens that cause bacterial in-
fections in children, including penicillin-resistant pneumo-
cocci. To provide dosing guidance for children, 3 single-dose,
multicenter pharmacokinetic studies were conducted in 85
children in 5 age groups: 6 months to <2 years, 2 to <5 years, 5
to <10 years, 10 to <12 years, and 12 to 16 years. Each child re-
ceived a single 7-mg/kg dose of levofloxacin (not to exceed
500 mg) intravenously or orally. Plasma and urine samples
were collected through 24 hours after dose. Pharmacokinetic
parameters were estimated and compared among the 5 age
groups and to previously collected adult data. Levofloxacin
absorption (as indicated by Cmax and tmax) and distribution in
children are not age dependent and are comparable to those
in adults. Levofloxacin elimination (reflected by t1/2 and
clearance), however, is age dependent. Children younger
L evofloxacin is a synthetic broad-spectrum fluoro-
quinolone antibacterial agent approved for use in
adults for the treatment of a variety of infections.1
Levofloxacin undergoes limited metabolism and dem-
onstrates linear pharmacokinetics in adults; its plasma
From Johnson & Johnson Pharmaceutical Research & Development, LLC,
Raritan, New Jersey (S. Chien, Dr Natarajan, Dr Maldonado, Dr Noel);
University of Arkansas for Medical Sciences and the Arkansas Children’s
Hospital PPRU, Little Rock, Arkansas (Dr Wells); Rainbow Babies and Chil-
dren’s Hospital PPRU, Cleveland, Ohio (Dr Blumer); University of Mis-
souri–Kansas City and the Children’s Mercy Hospitals and Clinics PPRU,
Kansas City, Missouri (Dr Kearns); Children’s Hospital and Health Center
and the UCSD/Children’s Hospital PPRU, San Diego, California (Dr
Bradley); Louisiana State University Health Sciences Center–Shreveport
and the Louisiana State University Health Sciences Center–Shreveport
PPRU, Shreveport, Louisiana (Dr Bocchini); and University of Medicine and
Dentistry of New Jersey, Newark, New Jersey (Dr Noel). This work was
funded by Johnson & Johnson Pharmaceutical Research and Develop-
ment, LLC, Raritan, New Jersey. Dr Kearns and Shuchean Chien are mem-
bers of the ACCP. Submitted for publication March 19, 2004; revised ver-
sion accepted October 7, 2004. Address for reprints: Shuchean Chien,
MS, Johnson & Johnson Pharmaceutical Research & Development, LLC,
920 Route 202 South, PO Box 300, Raritan, NJ 08869-0602.
DOI: 10.1177/0091270004271944
J Clin Pharmacol 2005;45:153-160
PEDIATRICS
than 5 years of age clear levofloxacin nearly twice as fast (in-
travenous dose, 0.32 0.08 L/h/kg; oral dose, 0.28 0.05 L/h/
kg) as adults and, as a result, have the total systemic expo-
sure (area under the plasma drug concentration-time curve)
approximately one half that of adults. The levofloxacin area
under the plasma drug concentration-time curve (dose nor-
malized) in children receiving a single dose of the oral liquid
formulation is comparable to that in children receiving the
intravenous formulation. To provide compatible levofloxacin
exposures associated with clinical effectiveness and safety in
adults, children 5 years need a daily dose of 10 mg/kg,
whereas children 6 months to <5 years should receive 10 mg/
kg every 12 hours.
Keywords: Levofloxacin; pediatrics; pharmacokinetics
Journal of Clinical Pharmacology, 2005;45:153-160
©2005 the American College of Clinical Pharmacology
protein binding is minimal and is concentration in-
dependent.2,3 Because exposure of juvenile laboratory
animals to some fluoroquinolones is associated with
formation of cartilage lesions, this class of antimicro-
bials is not widely accepted for routine use in chil-
dren.4,5 Despite this reluctance, fluoroquinolones have
been prescribed to treat difficult infections in chil-
dren.6-8 Reviews of this experience have yet to define a
specific toxicity of these agents that is unique to chil-
dren or to corroborate the animal data regarding ad-
verse cartilage effects. Given this experience and the
potential value of levofloxacin as an alternative agent
for children with infections caused by pathogens resis-
tant to broad-spectrum β-lactams and macrolides, there
is reason to examine levofloxacin pharmacokinetics in
pediatric patients. This is especially true given the
well-known alterations in drug disposition due to the
developmental differences in body composition (eg,
apparent volume of distribution) and the plasma clear-
ance of many drugs.9,10
To examine the potential age dependence in the
pharmacokinetics of levofloxacin, 3 single-dose phar-
153
 CHIEN ET AL
macokinetic studies were conducted in children from
the ages of 6 months to 16 years following either an in-
travenous or oral dose as a liquid formulation. Pharma-
cokinetic data were compared among 5 age groups (6
months to <2 years, 2 to <5 years, 5 to <10 years, 10 to
<12 years, and 12 to 16 years) and to previous data from
adults receiving a single 500-mg dose of levofloxacin
(~7 mg/kg for adults with average body weight of 70 kg)
that had demonstrated clinical effectiveness and
safety.
MATERIALS AND METHODS
Study Designs
Three studies were conducted to characterize the phar-
macokinetics of levofloxacin in children. Two open-
label studies administered a single intravenous (IV)
dose, and a third open-label study administered a sin-
gle oral (PO) dose of a liquid formulation of levoflox-
acin. Study 1 (IV dosing) was conducted with 20 hospi-
talized children, aged 6 months to 12 years. Study 2 (IV
dosing) involved 24 hospitalized children aged 8 to 16
years. Study 3 (PO dosing) involved 41 children, aged 6
months to 16 years. In all 3 studies, children either had
documented or presumed bacterial infections and
were receiving concomitant antimicrobial therapy pre-
scribed independently of the study protocol. Children
were housed in an appropriate hospital unit for at least
12 hours following administration of the study medica-
tion. Subject eligibility was restricted to those with no
evidence of clinically significant abnormal hematol-
ogy, serum chemistry (including assessment of albu-
min concentration, hepatic and renal function), or uri-
nalysis laboratory values. Subjects were excluded if
they were taking other quinolones or any other con-
comitant medication that might interfere with the
interpretation of the study results (eg, loop diuret-
ics, probenecid, cimetidine, or drugs or natural prod-
ucts known to induce or inhibit hepatic microsomal
enzymes).
Enrollment in each of these 3 studies was stratified
by age. Children in study 1 (n = 20; 6 months to <2
years, 2 to <5 years, 5 to <12 years) and study 2 (n = 24; 8
to <10 years, 10 to <12 years, and 12 to 16 years) re-
ceived a single 7-mg/kg dose of levofloxacin (final con-
centration 5 mg/mL; diluted in 5% dextrose and water
D5W) infused intravenously at a constant rate over 1
hour using a syringe pump with microbore tubing.
Children in study 3 (n = 41; 6 months to <2 years, 2 to
<5 years, 5 to <10 years, 10 to <12 years, and 12 to 16
years) received a single 7-mg/kg oral dose of levo-
floxacin suspension. Levofloxacin PO doses were ad-
154 • J Clin Pharmacol 2005;45:153-160
ministered with an age-appropriate volume of water
(90-120 mL at 4 °C) or clear liquids to ensure complete
delivery of the dose to the stomach. Subjects did not
have solid foods for at least 2 hours before and 2 hours
after dosing. Clear liquids, such as apple juice, were
permitted until 1 hour before and 1 hour after dose. All
study medication (both IV and PO formulations) was
derived from a single lot of levofloxacin so as to mini-
mize variability in drug potency between patients in a
given study. In all 3 pediatric investigations, the total
dose of levofloxacin did not exceed 500 mg.
In each study, blood samples (2.0 mL each) were ob-
tained at various time points during a 24-hour postdose
period through an indwelling venous cannula placed
in an extremity. For the intravenous study, blood sam-
ples were collected from an extremity contralateral to
the one used for levofloxacin infusion. When possible,
36- and 48-hour postdose blood samples were also col-
lected. Urine samples were collected by spontaneous
voiding from subjects who were toilet trained and who
could reliably provide quantitative collections. Blood
samples were collected into glass tubes containing so-
dium heparin, mixed by inversion, and were centri-
fuged at 2500 rpm for 10 minutes at room temperature.
Plasma was removed by manual aspiration, placed into
a screw-capped polypropylene vial, and frozen at ≤–20
°C until assay. Urine samples were collected, the vol-
ume and pH determined, and a 20-mL aliquot trans-
ferred to a polypropylene bottle and frozen at ≤–20 °C
until assay. Both plasma and urine samples were
analyzed within 6 months from collection.
The total concentration of levofloxacin in plasma or
in urine was determined by a validated high-perfor-
mance liquid chromatography (HPLC) method.11 The
method had a range of linearity from 0.08 to 5.12 µg/
mL, and the inter- and intra-assay precision values (ex-
pressed as percent coefficient of variation) were consis-
tently below 10% for all concentrations in the range of
linearity. The limit of quantification for the assay was
determined to be 82 ng/mL. The accuracy of the
method was reflected by measured concentrations of
the quality control samples that were consistently
within ±10% of the target concentrations. Stability of
samples (defined as <10% loss of initial concentration)
was previously verified through 2 years when main-
tained at ≤–20 °C. The assay was selective, and there
was no assay interference by the presence of concom-
itant medications.
Tolerability was evaluated by assessment of adverse
events, clinical laboratory tests, vital signs, and physi-
cal examinations. Complete physical examinations
were performed within 48 hours before and after dos-
ing. Vital signs were obtained immediately before
 LEVOFLOXACIN PHARMACOKINETICS IN CHILDREN
study drug administration and at the end of the study.
Clinical laboratory tests included hemoglobin,
hematocrit, red blood cell, white blood cell, and platelet
counts; serum glutamic-oxaloacetic transaminase, serum
glutamic-pyruvic transaminase, alkaline phosphatase,
total protein, total bilirubin, blood urea nitrogen, serum
albumin, serum creatinine, sodium, potassium, and
chloride levels; and gross and microscopic urinalyses.
Subjects were recruited at 5 study sites: University
of Arkansas for Medical Sciences and the Arkansas
Children’s Hospital PPRU, Little Rock, Arkansas; Rain-
bow Babies and Children’s Hospital PPRU, Cleveland,
Ohio; University of Missouri–Kansas City and the Chil-
dren’s Mercy Hospitals and Clinics PPRU, Kansas City,
Missouri; Children’s Hospital and Health Center and
the UCSD/Children’s Hospital PPRU, San Diego, Cali-
fornia; and Louisiana State University Health Sciences
Center–Shreveport and the Louisiana State University
Health Sciences Center–Shreveport PPRU, Shreveport,
Louisiana. Laboratory analysis of plasma and urine
samples was conducted at Johnson & Johnson Pharma-
ceutical Research and Development, LLC, Raritan,
New Jersey. Independent institutional review boards at
each study site reviewed the study protocol. Informed
consent was obtained from the parent or guardian and
assent from subjects age ≥7 years before the initiation of
any study-related procedures.
Pharmacokinetic Analysis
Levofloxacin plasma concentration-time data were
analyzed by standard noncompartmental methods.12
Pharmacokinetic parameters characterizing the ab-
sorption (Cmax, tmax), distribution (Vd), elimination (t1/2
and clearance [CL]), and total systemic exposure (area
under the plasma drug concentration-time curve
[AUC]) of levofloxacin in children were estimated. The
apparent Cmax and tmax values were estimated by visual
inspection of the plasma drug concentration-time data
for each subject. The AUC was obtained by the linear
trapezoidal rule up to the final measurable concentra-
tion (Cplast) and was extrapolated to infinity (AUC0-∞),
calculated as AUC0-last + Cplast/kel, where kel is the termi-
nal elimination rate constant (ie, the slope of the
plasma concentration-time profile at the terminal log-
linear phase, as determined by least squares linear re-
gression), and AUC0-last is the AUC from 0 hours to the
time corresponding to Cplast. Apparent total body clear-
ance (CL for IV and CL/F for PO) was determined as
dose/AUC0-∞. The terminal plasma elimination half-life
(t1/2) was calculated as 0.693/kel and the apparent vol-
ume of distribution (Vd) as CL/kel. The renal clearance
(CLR) was calculated by the equation Ae/AUC, where
PEDIATRICS
Ae is the cumulative amount of drug excreted within
the sampling interval, and AUC is the AUC of the drug
in plasma extrapolated to the end of the urine col-
lection period. For comparison, pharmacokinetic data
from adult male volunteers (aged 18-53 years) were in-
cluded that were derived from previously published
methods.13
Statistical Analysis
Pharmacokinetics of levofloxacin in children was com-
pared among the 5 age groups (6 months to <2 years, 2
to <5 years, 5 to <10 years, 10 to <12 years, and 12 to 16
years) and to data collected from separate studies in
which healthy fasting adults received a single 500-mg
levofloxacin dose (approximately equivalent to 7 mg/
kg) in either the IV (20-40 years, n = 23; 1-hour IV infu-
sion) or PO liquid formulation (19-55 years, n = 36).
The pharmacokinetic parameters of interest for the sta-
tistical analysis were Cmax, CL, and Vd. Because AUC is
correlated with CL to a constant value (ie, CL = dose/
AUC), a separate statistical analysis for AUC was not
performed. The analysis of variance models was fit to
the data with one of the pharmacokinetic parameters as
the dependent variable and the age group as the cate-
gorical predictor. The age group effect was tested at the
5% level of significance. If the age group effect was
found to be significant, then the pairwise comparisons
for age groups were tested at a level of significance of α
= 0.003 for each pairwise test (overall 5% level of sig-
nificance). Statistics were performed using SAS
Version 6.12 (SAS Institute, Cary, NC).
RESULTS
Patient Population
Eighty-five children (20, 24, and 41 in studies 1, 2, and
3, respectively) ranging from 6 months to 16 years of
age were enrolled and completed the study, and thus
they were evaluated for tolerability. Eighty subjects
had sufficient concentration-time data to accurately
determine pharmacokinetic parameters and conse-
quently were included in the pharmacokinetic evalua-
tion. The 5 subjects not included in the pharma-
cokinetic evaluation included 1 subject from study 1
(withdrew from the study immediately after dose and
before any pharmacokinetic sample was collected), 3
from study 2 (pharmacokinetic sample labels fell off
during shipment), and 1 from study 3 (vomited imme-
diately after receiving study drug and was withdrawn
from the study). Demographics and baseline character-
istics of the 80 pharmacokinetically evaluable children
155
 CHIEN ET AL

Table I Demographic and Baseline Characteristics of

the 80 Pharmacokinetically Evaluable Subjects
Age Group, y Gender Weight, kg CLCR, mL/min

IV
0.5 to <2 1F, 5M
Mean 9.4 189.7 ± 89.0
Range 6.4-11.6
2 to <5 5F, 2M
Mean 13.7 193.8 ± 164.7
Range 12.4-16.5
5 to <10 6F, 4M
Mean 24.9 164.5 ± 59.9
Range 10.2-37.3
10 to <12 6F, 1M Figure 1. Mean values of levofloxacin plasma concentration versus
time profiles in children and adults receiving a single intravenous
Mean 45.1 137.4 ± 26.6 (IV) dose of levofloxacin (children, 7 mg/kg; adults, 500 mg). Each
Range 35.9-58.2 symbol indicates the mean plasma concentration for subjects in the
12 to 16 5F, 5M corresponding age group.
Mean 57.5 149.5 ± 34.7
Range 39.9-84.1
PO
0.5 to <2 3F, 5M
Mean 11.0 145.5 ± 29.1
Range 8.8-13.5
2 to <5 6F, 2M
Mean 15.6 172.0 ± 54.3
Range 12.7-21.8
5 to <10 3F, 5M
Mean 26.1 156.3 ± 38.5
Range 17.7-39.5
10 to <12 5F, 3M
Mean 42.5 144.5 ± 24.1
Range 26.4-68.2
12 to <16 6F, 2M
Mean 60.7 134.9 ± 26.0
Range 47.9-81.6
IV, intravenous dose; PO, oral dose. Creatinine clearance (CLCR) presented Figure 2. Mean values of levofloxacin plasma concentration versus
as mean ± SD. CLCR was calculated using the Schwartz formula.17 time profiles in children and adults receiving a single oral (PO) dose
of levofloxacin (children, 7 mg/kg; adults, 500 mg). Each symbol indi-
cates data for subjects in the corresponding age group.

are provided in Table I. In general, levofloxacin was

well tolerated, and no severe adverse events were
reported by any of the participants during the study
period.
Pharmacokinetics
The mean plasma levofloxacin concentration-time
profiles for each age group receiving either the IV or PO
dose are illustrated in Figures 1 and 2, respectively. Re-
gardless of the route of drug administration, the pro-
files for infants (6 months to 2 years old) and younger
children (2 to 5 years old) were found to be nearly
superimposable, as were the profiles between children
10 to 12 years old and children 12 to 16 years old. When
comparing levofloxacin plasma concentration profiles
resulting from the PO and IV administrations, each of
the age groups showed similar profiles after the initial
time points (ie, from 0 to 2 hours).
The levofloxacin pharmacokinetic parameters after
IV and PO dosing for each of the 5 pediatric age groups
and for adults are shown in Table II. The statistical test
results from intergroup comparison using ANOVA are
presented in Tables III and IV. No age-dependent differ-

156 • J Clin Pharmacol 2005;45:153-160

 LEVOFLOXACIN PHARMACOKINETICS IN CHILDREN

Table II Summary of Levofloxacin Pharmacokinetic Estimates in Children Receiving a Single Dose (7 mg/kg)

Age Group, y n Cmax, µg/mL AUC0-∞, µg•h/mL t1/2, h tmax, h VDss/F, L/kg CL/F, L/h/kg

Children; single 7-mg/kg dose (to max 500 mg)

0.5 to 2
IV 6 5.19 ± 1.26 21.5 ± 6.1 4.1 ± 1.3 1 1.56 ± 0.30 0.35 ± 0.13
PO 8 4.21 ± 1.49 25.8 ± 9.2 5.0 ± 1.3 1.4 ± 0.4 2.32 ± 1.41 0.31 ± 0.13
2 to 5
IV 7 6.02 ± 1.07 22.7 ± 4.7 4.0 ± 0.8 1 1.50 ± 0.21 0.32 ± 0.08
PO 8 4.56 ± 0.83 25.9 ± 4.8 4.6 ± 1.3 1.6 ± 0.5 1.81 ± 0.62 0.28 ± 0.05
5 to 10
IV 10 7.30 ± 3.85 29.2 ± 6.4 4.8 ± 0.8 1 1.57 ± 0.44 0.25 ± 0.05
PO 8 4.64 ± 0.39 29.0 ± 10.0 5.3 ± 1.6 1.3 ± 0.4 1.88 ± 0.44 0.26 ± 0.06
10 to 12
IV 7 6.12 ± 1.19 39.8 ± 11.3 5.4 ± 0.8 1 1.44 ± 0.35 0.19 ± 0.05
PO 8 3.99 ± 0.87 37.3 ± 9.8 5.5 ± 0.7 1.9 ± 0.9 1.57 ± 0.43 0.20 ± 0.06
12 to 16
IV 10 6.34 ± 1.58 40.5 ± 7.6 6.0 ± 2.1 1 1.56 ± 0.53 0.18 ± 0.03
PO 8 4.76 ± 0.86 41.1 ± 6.8 5.8 ± 1.4 1.6 ± 1.0 1.40 ± 0.28 0.17 ± 0.04

Adults; single 500-mg dosea

IV 23 6.18 ± 1.04 48.3 ± 5.40 6.0 ± 1.0 1 1.27 ± 0.12 0.15 ± 0.02
PO 36 5.41 ± 1.68 49.3 ± 12.5 6.9 ± 1.5 1.1 ± 0.9 1.44 ± 0.40 0.14 ± 0.03
All data presented as mean ± SD. IV, intravenous dose; PO, oral dose; Cmax, maximum concentration; AUC0-∞, area under the concentration-time curve from 0 to
infinity; t1/2, half-life; tmax, time to achieve Cmax; VDss/F, volume of distribution at steady state/bioavailability; CL/F, clearance/bioavailability.
a. Data on file, Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey.

ence was observed for Cmax between the 5 age groups Table III Testing for Age Group Effect
and adults (P = .194). When Vd was normalized by
body weight, the pairwise comparisons were found not Parameter MSE F df P Value
to be significantly different, except the comparison be-
CL, L/h•kg 0.003 37.30 (5, 133) <.001a
tween children <2 years of age and adults (P = .0002). In
Vd, L/kg 0.268 3.57 (5, 133) .005a
contrast, levofloxacin apparent total body clearance Cmax, µg/mL 3.119 1.50 (5, 133) .194
(CL or CL/F, normalized by body weight) was shown to
CL, clearance; Vd, distribution; Cmax, maximum concentration; MSE, mean
vary as a consequence of age until approximately 10 square error.
years of age (Tables II to IV). a. Denotes significant at α = 0.05 level of significance.

Safety
No subjects experienced a drug-related adverse event
that was considered serious or life threatening, and no
tendon- or joint-related adverse events were observed.
All of the reported treatment-emergent adverse events
were considered by the investigator to be mild or mod-
erate in severity. There was 1 serious adverse event of
wound dehiscence, but this was judged by the investi-
gator to not be drug related. Proteinuria, indicated by
positive dipstick, occurred in 2 patients but was re-
solved spontaneously upon repeat evaluation. There
were no clinically significant changes in laboratory
values from the predose to postdose evaluations.
DISCUSSION
The results of these single-dose studies indicate that,
with the exception of CL or CL/F, the pharmacokinetics
of levofloxacin did not appear to vary as a consequence
of age between 6 months and 16 years (Table II). The ap-
parent total body clearance of levofloxacin was in-
versely associated with age (Table II, Figure 3). Specifi-

PEDIATRICS 157
 CHIEN ET AL

Table IV Testing for Significance of Difference of Least Squares Means for Age Group
Parameter Age Group 2 to <5 Years 5 to <10 Years 10 to <12 Years 12 to 16 Years Adult

CL, L/h•kg <2 NS S S S S

2 to <5 — NS S S S
5 to <10 — NS S S
10 to <12 — NS NS
12 to 16 — NS
Vd, L/kg <2 NS NS NS NS S
2 to <5 — NS NS NS NS
5 to <10 — NS NS NS
10 to <12 — NS NS
12 to 16 — NS
Vd, distribution; CL, clearance; NS, not significant at an overall α = 0.05 level of significance; S, significant at an overall α = 0.05 level of significance.

cally, clearance consistently decreased with age until

10 years of age (IV, 0.35 ± 0.13 to 0.19 ± 0.05 L/h•kg; PO,
0.31 ± 0.13 to 0.20 ± 0.06 L/h•kg; Table II), where it sta-
bilized to values slightly higher than those previously
observed in adults (IV, 0.15 ± 0.02 L/h•kg; PO, 0.14 ±
0.03 L/h•kg; Table II). When an inverse first-order non-
linear regression curve fit was applied to the apparent
total body clearance versus age profiles, it was ob-
served that the most significant change occurred dur-
ing the first 1 to 2 years of age; the decrease slowed
down afterward and stabilized at 10 years of age (Fig-
ure 3). This phenomenon may be explained by the fact
that levofloxacin is minimally metabolized and pri-
marily excreted renally as an unchanged drug. In view
of the fact that the developmental profile for the acqui-
sition of the glomerular filtration rate reflects the at-
tainment of maturity over the first 1 to 2 years of age,14 Figure 3. Apparent total body clearance versus age profiles in chil-
the pattern for age dependence in levofloxacin appar- dren and adults receiving a single dose of levofloxacin (children, 7
ent clearance found in the present study (Figure 3) was mg/kg; adults, 500 mg). Values are shown for subjects after an intra-
venous (filled circles) or oral dose (open circles).
expected. Children younger than 5 years of age cleared
levofloxacin nearly twice as fast (IV, 0.32 ± 0.08 L/h•kg;
PO, 0.28 ± 0.05 L/h•kg; Table II) as adults and, as a
result, had a total systemic exposure (AUC) Levofloxacin exhibits concentration-dependent
approximately one half that of adults (Table II). bactericidal activity, and clinical outcomes are related
The results from the current investigation also dem- to the ratios of AUC/MIC or Cmax/MIC. To identify a dosing
onstrate that the apparent bioavailability of regimen that provides comparable levofloxacin expo-
levofloxacin in children was virtually 100% (Table II; sures between adults and children, a pharmacokinetic/
mean AUC ratios between the PO and IV administra- pharmacodynamic (PK/PD) modeling approach was
tions were 120%, 114%, 99%, 94%, and 101% for 6 applied. An optimal dosing regimen can be based on
months to <2 years, 2 to <5 years, 5 to <10 years, 10 to the following criteria: (1) achieving a steady-state Cmax
<12 years, and 12 to 16 years, respectively) and was and AUC that do not exceed the Cmax or AUC that have
compatible with the absolute bioavailability (99%- been shown to be well tolerated by adults,15 (2) achiev-
103%) observed from the adults receiving the same ing a steady-state Cmax/MIC that has been shown to be
oral liquid formulation in a crossover bioavailability effective in treating adults,16 and (3) approximating
study (Johnson & Johnson Pharmaceutical Research & 70% to 130% the steady-state AUC/MIC that has been
Development, LLC; data on file). shown to be associated with effectiveness in adults.

158 • J Clin Pharmacol 2005;45:153-160

 LEVOFLOXACIN PHARMACOKINETICS IN CHILDREN

Table V Pharmacokinetic Estimates of the 2-Compartment Pharmacokinetic Model Used in

Dosing Regimen Simulation
6 Months to <5 Years 5 to <10 Years 10 to 16 Years

Volume, L/kg 0.69 0.68 0.93

K10, h–1 0.50 0.38 0.20
K12, h–1 1.52 1.31 0.19
K21, h–1 1.75 1.50 0.41
K10, K12, and K21 are first-order intercompartmental transfer rate constants.

Table VI Predicted Levofloxacin Steady-State Drug Exposures in Children Under the

Recommended Dosing Regimens
Adults
6 Months to <5 Years, 5 to <10 Years, 10 to 16 Years,
a b
10 mg/kg bid 10 mg/kg qd 10 mg/kg qd 500 mg qd 750 mg qd

AUC0-24h, µg•h/mL 58.4 38.4 54.8 54.6 ± 11.1c 91.0 ± 18.0c

Cmax, µg/mL 8.37 8.80 9.35 6.40 ± 0.80c 8.60 ± 1.86c
a. Recommended adult dose for the treatment of community-acquired pneumonia.
b. Recommended adult dose for the treatment of complicated skin and skin structure infections.
c. Observed data in healthy adults, as reported on the Levaquin package insert.

Data collected from the 3 studies indicate that a 2-com-
partment pharmacokinetic model with constant input
and first-order output (parameters listed in Table V),
which passed the goodness-of-fit and the Akaike and
Schwartz model selection criteria, is most appropriate
for dosing regimen simulation for children. On the ba-
sis of this PK/PD model, children of older age (≥5 years)
would require a 10-mg/kg body weight dose once daily,
whereas children of younger age (6 months to <5 years)
should receive a 10-mg/kg dose every 12 hours. Pre-
dicted steady-state levofloxacin exposures in children
under these dosing regimens are presented in Table VI.
Safety, efficacy, and population pharmacokinetics of
these dosing regimens are currently being evaluated in
children 6 months to 16 years of age. Population
pharmacokinetic analysis will provide important con-
firmation, particularly because the sample size for each
group in the current study was small. It is also impor-
tant to recognize that these recommendations should
not be extrapolated to infants younger than 6 months of
age, a population that has not yet been studied.
The study results demonstrate that an age-dependent
difference in total body clearance of levofloxacin oc-
curs at a magnitude sufficient to warrant age-specific
dosing regimens. Extrapolation of dosing in children
based on the defined pharmacokinetics of levofloxacin
in adults may result in insufficient drug exposure in
children, especially for those younger than 5 years of
age.
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