ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2009, p. 34623471 Vol. 53, No.

8
0066-4804/09/$08.000 doi:10.1128/AAC.00054-09
Copyright 2009, American Society for Microbiology. All Rights Reserved.

New Semiphysiological Absorption Model To Assess the Pharmacodynamic

Profile of Cefuroxime Axetil Using Nonparametric and Parametric
Population Pharmacokinetics
J. B. Bulitta,1 C. B. Landersdorfer,1 M. Kinzig,1 U. Holzgrabe,2 and F. Sorgel1,3*
Institute for Biomedical and Pharmaceutical Research (IBMP), Nurnberg-Heroldsberg, Germany1; Institute of Pharmacy and
Food Chemistry, University of Wurzburg, Wurzburg, Germany2; and Department of Pharmacology, University of
DuisburgEssen, Essen, Germany3

Downloaded from http://aac.asm.org/ on February 5, 2017 by GLAXOSMITHKLINE

Received 14 January 2009/Returned for modification 26 March 2009/Accepted 3 June 2009

Cefuroxime axetil is widely used to treat respiratory tract infections. We are not aware of a population
pharmacokinetic (PK) model for cefuroxime axetil. Our objectives were to develop a semiphysiological popu-
lation PK model and evaluate the pharmacodynamic profile for cefuroxime axetil. Twenty-four healthy volun-
teers received 250 mg oral cefuroxime as a suspension after a standardized breakfast. Liquid chromatography-
tandem mass spectrometry was used for drug analysis, NONMEM and S-ADAPT (results reported) were used
for parametric population PK modeling, and NPAG was used for nonparametric population PK modeling.
Monte Carlo simulations were used to predict the duration for which the non-protein-bound-plasma concen-
tration was above the MIC (fT>MIC). A model with one disposition compartment, a saturable and time-
dependent drug release from the stomach, and fast drug absorption from the intestine yielded precise (r >
0.992) and unbiased curve fits and an excellent predictive performance. The apparent clearance was 21.7
liters/h (19.8% coefficient of variation [CV]) and the volume of distribution 38.7 liters (18.3% CV). Robust
(>90%) probabilities of target attainment (PTAs) were achieved by 250 mg cefuroxime given every 12 h (q12h)
or q8h for MICs of <0.375 mg/liter or <0.5 mg/liter, respectively, for the bacteriostasis target fT>MIC of >40%
and for MICs of <0.094 mg/liter or <0.375 mg/liter, respectively, for the near-maximal-killing target fT>MIC
of >65%. For the >40% fT>MIC target, the PTAs for 250 mg cefuroxime q12h were >97.8% for Streptococcus
pyogenes and penicillin-susceptible Streptococcus pneumoniae. Cefuroxime at 250 mg q12h or q8h achieved PTAs
below 73% or 92%, respectively, for Haemophilus influenzae, Moraxella catarrhalis, and penicillin-intermediate
S. pneumoniae for susceptibility data from various countries. Depending on the MIC distribution, 250 mg oral
cefuroxime q8h instead of q12h should be considered, especially for more-severe infections that require
near-maximal killing by cefuroxime.

Cefuroxime axetil is the acetoxyethyl-ester prodrug of cefu-
roxime. Cefuroxime axetil is reliably absorbed and can be taken
with or without a meal, although its extent of bioavailability is
enhanced under the influence of food (20, 54). Cefuroxime has
been successfully used in the treatment of upper and lower
respiratory tract infections as well as genitourinary tract
infections (45) and is active against Haemophilus influenzae,
Moraxella catarrhalis, Streptococcus pyogenes, Klebsiella pneu-
moniae, Neisseria gonorrhoeae, penicillin-susceptible Strepto-
coccus pneumoniae, and some isolates of penicillin-intermedi-
ate S. pneumoniae (6, 7, 2527, 34, 35, 37, 38, 41, 55).
A susceptibility breakpoint of 1 mg/liter has been determined
for cefuroxime by national organizations in Britain (BSAC) (8)
and Germany (DIN) (17). The susceptibility breakpoints from
the Clinical and Laboratory Standards Institute (CLSI) (11)
* Corresponding author. Mailing address: Institute for Biomedical
and Pharmaceutical Research (IBMP), Paul-Ehrlich-Str. 19, D-90562
Nurnberg-Heroldsberg, Germany. Phone: 49-911-518290. Fax: 49-911-
5182920. E-mail: ibmp@osn.de.
This article is dedicated to Ulrich Stephan, the cofounder of
IBMP, who passed away on 6 February 2009. Without his inspiration
and support, IBMP would not exist, and neither would the present
research have been performed. We keep him in our hearts.
Present address: Ordway Research Institute, Albany, NY 12208.
Published ahead of print on 15 June 2009.
are 1 mg/liter for S. pneumoniae and 4 mg/liter for Hae-
mophilus spp., Enterobacteriaceae, and Staphylococcus spp.
Several authors (31, 37, 40) determined the pharmacoki-
netic-pharmacodynamic (PK-PD) MIC breakpoint for cefu-
roxime axetil on the basis of the average plasma concentration
profiles but did not incorporate between-subject variability
(BSV) in their analysis. Ambrose et al. (2) determined the
PK-PD MIC breakpoint for intravenous cefuroxime via Monte
Carlo simulation (MCS) based on literature data, and Viberg
et al. (51, 52) developed a population PK model for intrave-
nous cefuroxime. We are not aware of a population PK model
or MCS for cefuroxime axetil.
Population PK and the MCS methodology account for the
BSV in PK parameters and for the variability in the bacterial
susceptibility. A PK-PD target is used as a surrogate measure
to predict successful microbiological or clinical outcome (13,
18, 22, 28, 29, 48). For beta-lactams, the duration for which the
non-protein-bound-plasma concentration exceeds the MIC
(fTMIC) best predicts these outcomes (3, 14, 18). For cepha-
losporins, data from animal infection models showed that a
target fTMIC of 40% correlates with bacteriostasis at 24 h and
that an fTMIC of 60 to 70% is required for near-maximal
bactericidal activity at 24 h (3, 12, 14, 18). On the basis of these
PK-PD targets, MCS can predict the probability of target at-
tainment (PTA) at various MICs. If the PTA-versus-MIC pro-

3462
VOL. 53, 2009
file is combined with the expected MIC distribution of the
pathogen(s) of interest in a local hospital, the probability of
successful microbiological or clinical outcome can be pre-
dicted.
In addition to increasing the extent of bioavailability (20,
54), administration after a meal may cause a lower rate of
cefuroxime absorption due to a prolonged gastric transit time.
The rate of gastric emptying after a high-fat meal is likely to be
variable and may change over time. Parameters describing the
absorption phase may also not be normally or log-normally
distributed. As MCS based on parametric population PK mod-
els uses parametric distributions to describe the variability in
PK parameters, we additionally applied nonparametric popu-
lation PK modeling. The latter offers the advantage that it does
not assume any shape for the multivariate distribution of PK
parameters. However, sample sizes larger than 24 subjects may
be required to adequately describe the shape of the multivar-
iate distribution by a nonparametric variability model.
Our first objective was to develop a semiphysiological
population PK model for cefuroxime axetil by using para-
metric and nonparametric population PK methods. Second,
we sought to determine the PTA-versus-MIC profiles and
the PTAs for specific MIC distributions of various patho-
gens for dosage regimens with oral cefuroxime given every
12 h (q12h) or q8h.
(This work was presented in part at the 46th Interscience
Conference on Antimicrobial Agents and Chemotherapy, 2006
[8a].)
MATERIALS AND METHODS
Subjects. Twenty-four healthy male Caucasian volunteers participated in the
study after they had given their written informed consent. Their demographic
data were as follows (means standard deviations [SD]): age, 24.5 3.3 years
(range, 18 to 31 years); weight, 73.8 9.2 kg (range, 58.2 to 93.6 kg); and height,
179 8.0 cm (range, 166 to 193 cm). The subjects health statuses were assessed
by physical examination, electrocardiography, and laboratory tests, including
urinalysis and screening for drugs of abuse. Intake of food and fluid was strictly
standardized during the study days. Consumption of tobacco, methylxanthines,
and alcohol in any form was prohibited from 12 h before administration of the
study drug until acquisition of the last sample. The volunteers were closely
observed by physicians for the occurrence of adverse events on the study days.
The study protocol had been approved by the local ethics committee, and the
study was conducted by following the revised version of the Declaration of
Helsinki.
Study design and drug administration. The study was a single-dose, single-
center study. All subjects received an oral suspension of 300.72 mg cefuroxime
axetil (equivalent to 250 mg cefuroxime) with 240 ml low-carbonated, calcium-
poor mineral water at room temperature. The study drug was administered
directly after intake of a standardized breakfast with a significant amount of fat.
This breakfast contained four slices of crisp bread (50 g), 20 g margarine, 2 slices
of cheese (40 g; 30% fat content), 25 g jam, 100 ml fruit tea, and 100 ml milk
(3.5% fat content).
Blood sampling. All blood samples were drawn in heparinated tubes from a
forearm vein via an intravenous catheter. Blood samples were drawn immedi-
ately before administration and at 30, 60, and 90 min and at 2, 2.33, 2.67, 3, 3.33,
3.67, 4, 4.5, 5, 6, 8, 10, and 12 h after administration of the study drug. Samples
were immediately centrifuged and immediately frozen and stored at 70C until
analysis.
Drug analysis. Samples were analyzed by means of a liquid chromatography-
tandem mass spectrometry method validated for 0.1-ml samples of human
plasma. Plasma samples (0.1 ml) were diluted with buffer containing the internal
standard and deproteinized by addition of 400 l of acetonitrile. After thorough
mixing, the samples were centrifuged for 5 min at 3,600 rpm at approximately
4C, and acetonitrile was removed by extraction with 1 ml dichloromethane.
The mixture was centrifuged again, and 30 l of the aqueous phase of each
sample was then chromatographed on a reversed-phase column (Waters Sym-
POPULATION PK AND PD OF CEFUROXIME AXETIL 3463
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FIG. 1. Structure of the final PK model. For the simulation of
Vmax/Vmax 0 profiles, Emax values of 3 (long dashed line), 1 (continuous
line), or 0.5 (dotted line); a TC50 of 2.5 h; and a Hill coefficient of 10
were used. CL, clearance. (See Table 2 and Materials and Methods for
further explanations of the parameters.)
metry C8), eluted with an isocratic solvent system consisting of ammonium
acetate buffer and acetonitrile (70%-30%, vol/vol), and monitored by liquid
chromatography-tandem mass spectrometry with a multiple-reaction-monitoring
method as follows: precursor 3 product ion for cefuroxime (m/z 423 3 m/z 207)
and an internal standard (m/z 426 3 m/z 156). Both analyses were in negative
mode. Under these conditions, cefuroxime and the internal standard were eluted
after approximately 1.4 and 1.5 min. The Mac Quan software program (version
1.5; PE Sciex, Thornhill, Ontario, Canada [1991 to 1997]) was used for evaluation
of chromatograms.
The linearity of the cefuroxime calibration curve was shown from 0.00900
mg/liter to 10.2 mg/liter. The coefficient of correlation for all measured se-
quences of cefuroxime was at least 0.999. The lowest calibration standard of
0.00900 mg/liter was set as the lower limit of quantification of the assay for
cefuroxime in human plasma. There was no observation below this quantification
limit. For the spiked quality control standards of cefuroxime, the interday pre-
cision ranged from 3.2 to 5.0%, with interday accuracy (relative error) between
4.3 and 2.1%. The intraday precision and relative error of the cefuroxime assay
ranged from 0.7 to 4.0% and from 0.1 to 3.4%, respectively.
Population PK analysis. (i) Computation. We applied the first-order condi-
tional estimation method with the interaction estimation option in NONMEM,
version VI, release 1.2 (NONMEM Project Group, University of California, San
Francisco) (5). Initial models were developed in NONMEM V. Model develop-
ment was primarily performed in NONMEM. The final population PK model
was additionally estimated in S-ADAPT (version 1.55; parallelized on a com-
puter cluster), using the importance-sampling parametric Monte Carlo expecta-
tion maximization method (with a pmethod value of 8 in S-ADAPT) (4) and by
the nonparametric adaptive grid (NPAG) algorithm implemented in the
USC*PACK program (version 12.00) (33). WinNonlin Professional (version
4.0.1; Pharsight Corp., Mountain View, CA) was used for noncompartmental
analysis and statistics.
Parameter uncertainty was assessed by standard asymptotic formulas in S-
ADAPT (4). As NONMEM could not compute asymptotic standard errors in the
$COV step for the final model, nonparametric bootstrap methods with 100
replicates were used to calculate standard errors in NONMEM as described
previously (9).
(ii) Structural model. We considered one- and two-compartment disposition
models with first-order, zero-order, or mixed-order (Michaelis-Menten) absorp-
tion with or without a lag time. Additionally, a semiphysiological model with a
time-dependent release from the stomach to the intestine and subsequent ab-
sorption into the central compartment was developed (Fig. 1). The differential
equations for this model are as follows:
dA1 Vmax A1
(1)
dt Km A1
dA2 Vmax A1
kabs A2 (2)
dt Km A1
dA3 CL
kabs A2 A3 (3)
dt V
where A1 is the amount of drug in the stomach, A2 is the amount of drug in the
intestine, and A3 is the amount in the central compartment (see Table 2 for
3464 BULITTA ET AL.
parameter explanations). All initial conditions for all three compartments were
zero. The stomach compartment (A1) received a bolus dose of 250 mg cefu-
roxime at zero hour. The model is simplified, as it did not contain a specific
compartment for the prodrug cefuroxime axetil. It was assumed that cefuroxime
axetil is converted to cefuroxime before the ester prodrug reaches the peripheral
sampling site. This assumption is considered justifiable for an ester prodrug. The
maximum rate of release (Vmax) of drug from the stomach compartment was
described by a time-dependent function:
VmaxTPM Vmax 0 1
Emax TPM
TC50 TPM (4)
Time is denoted as time past meal (TPM). Starting from a Vmax at time zero
(Vmax 0), the Hill coefficient () modifies the Vmax over time, with TC50 denoting
the time past the meal at which Vmax changed by 50% and Emax the extent of the
change in Vmax. For TPM values of TC50, the Vmax approaches Vmax 0 (1
Emax). Therefore, an Emax of 1 represents complete inhibition of gastric re-
lease, an Emax of 0 an unchanged maximum rate of gastric release, and an Emax
of 1 a maximum rate of gastric release twice as fast.
Competing models were discriminated by their predictive performance as-
sessed via visual predictive checks (VPCs), their objective function (or log like-
lihood), and standard diagnostic plots.
(iii) Parameter variability and observation model. For parametric population
PK modeling in NONMEM and S-ADAPT, we estimated the BSV of PK pa-
rameters by assuming a log-normal distribution. The maximum extent of inhibi-
tion or stimulation of gastric release for the ith subject (Emax i) was constrained
to a lower bound of 1 by the following logit transformation:
Emax i 1 10
expLg_Emax BSV Emax i
1 expLg_Emax BSV Emax i (5)
Lg_Emax is the estimated population mean (arithmetic mean) on the transformed
scale and BSV Emax i the random deviate for the ith subject on transformed scale.
This transformation ensures that all Emax i values range from 1 to 9. A sensi-
tivity analysis showed that the upper limit of 9 did not affect the curve fits or
predictive performance of this model.
Plasma concentration time profiles were simulated for at least 4,800 subjects
for each competing model to calculate the median and nonparametric 80%
prediction interval (10th to 90th percentile) for the predicted concentrations.
The same percentiles were calculated for the observations to visually assess
whether the simulated percentiles closely matched the percentiles of the obser-
vations. For nonparametric population PK models in NPAG, this VPC was
performed either based on the nonparametric distribution of PK parameters
characterized by the support point matrix or based on a parametric, multivariate
log-normal distribution of PK parameters. In all three programs full variance-
covariance matrices were estimated and used for MCS.
The residual unidentified variability was described by a combined additive and
proportional error model. We used the adaptive gamma option in NPAG to
estimate the residual error described by the assay error polynomial.
(iv) MCS. A target fTMIC of 60 to 70% has been identified for near-maximal
bactericidal activity of cephalosporins, and a target of 40% is required for
bacteriostasis (14, 18). Therefore, we used PK-PD target fTMICs of 65% for
near-maximal bactericidal activity and 40% for bacteriostasis. A range of MICs
from 0.031 to 64 mg/liter was considered. As the protein binding levels for
cefuroxime have been reported to range between 33 and 50% (21, 23, 45), we
assumed an average protein binding of 42% for cefuroxime.
We compared dosage regimens of 250 mg and 500 mg oral cefuroxime given
q12h and q8h at steady state. For the final population PK models in NONMEM,
S-ADAPT, and NPAG, we simulated 10,000 subjects for each dosage regimen in
the absence of residual error. NONMEM was used to simulate the full concen-
tration time profiles at steady state with very frequent sampling based on the final
population PK model and the estimated full variance-covariance matrix. The
fTMIC values were calculated by linear interpolation between simulated time
points as previously described (9).
The PTA was estimated by calculating the fraction of subjects who attained the
PK-PD target at each MIC. The highest MIC with a PTA of at least 90% was
used as the PK-PD MIC breakpoint.
To put these PTAs into clinical perspective, we calculated the PTA expecta-
tion value (39) for successful treatment against pathogens from specific MIC
distributions as described previously (9). The PTA expectation value is the PTA
for treatment of infections caused by bacteria from a specific MIC distribution
(ideally the MIC distribution of each local hospital).
The PTA expectation value was calculated based on published MIC distribu-
tions. We used susceptibility data from the United Kingdom (38) collected in
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. PK parameters for noncompartmental analysis for
250 mg oral cefuroxime given as cefuroxime axetil
Parameter Avg SDa Median (range)
Area under the curve from 11.9 2.49 11.6 (8.4918.1)
time zero to infinity
(mg/h/liter)
Peak concn (mg/liter) 2.64 0.64 2.54 (1.653.90)
Time of peak concn (h)
Terminal half-life (h)
Apparent total clearance
2.98 0.73
1.34 0.13
21.8 4.29
2.83 (2.005.00)
1.35 (1.081.54)
21.5 (13.829.4)
(liters/h)
Apparent vol of distribution at 54.1 15.7 51.2 (34.7102)
steady statea (liters)
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Apparent vol of distribution 41.7 7.64 44.4 (27.454.9)
during the terminal phase
(liters)
Time of total concn above 4.97 0.79 4.90 (3.437.08)
1 mg/liter (h)
Time of total concn above 6.90 0.77 6.75 (5.139.02)
0.5 mg/liter (h)
a
To calculate the mean residence time after intravenous bolus administration,
mean input time was estimated as 0.5 times the time of peak concentration,
assuming approximately zero-order kinetics of drug input.
2002 and 2003 for H. influenzae (n 581), M. catarrhalis (n 269), and S.
pneumoniae (n 519); susceptibility data from Canada (55) collected in 2001
and 2002 for H. influenzae (n 1,350); and susceptibility data from Germany (7)
collected in 2002 for H. influenzae (n 300), M. catarrhalis (n 308), S.
pneumoniae (n 331), and S. pyogenes (n 340). Additionally, we used sus-
ceptibility data from a global surveillance study (6) collected between 1997 and
2000 for penicillin-susceptible S. pneumoniae (n 2,102) and penicillin-inter-
mediate S. pneumoniae (n 1,024); susceptibility data from a European surveil-
lance study (26) collected between 1997 and 1999 for S. pneumoniae (n 2,018)
and S. pyogenes (n 662); and susceptibility data from North America (25)
collected between 1997 and 1999 for S. pyogenes (n 119), S. pneumoniae (n
417), H. influenzae (n 300), and M. catarrhalis (n 231). The PTA expectation
values were also calculated for the MIC distributions for H. influenzae (n
66,947), K. pneumoniae (n 34,629), M. catarrhalis (n 14,308), Staphylococcus
aureus (n 10,620), N. gonorrhoeae (n 655), and Neisseria meningitidis (n
257) on the basis of the multinational database of the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) (http://www.eucast.org/mic
_distributions_of_wild_type_microorganisms/).
RESULTS
The PK parameters from noncompartmental analysis (Table
1) were in good agreement with the literature (41, 45). We
found (average SD) a terminal half-life of 1.34 0.13 h and
a peak concentration of 2.64 0.64 mg/liter between 2 and 5 h
postdose. The variability in terminal half-life (9.4% coefficient
of variation) was lower than the variabilities in apparent clear-
ance (20%), peak concentration (24%), and time of peak
(24%).
A biphasic absorption pattern was found for 5 of 24 subjects
and a plateau-like peak for 8 of 24 subjects (Fig. 2). These
shapes could not be described by standard first-order or zero-
order absorption models that included a lag time. Compared to
the objective function value for the final semiphysiological
model, the objective function differences in NONMEM were
721 points for the first-order absorption model with a lag time,
359 points for the zero-order absorption model with a lag time,
and 189 points for the Michaelis-Menten absorption model
with a lag time (likelihood ratio test: P 0.0001 for all com-
parisons). The semiphysiological absorption model with a two-
compartment disposition model had a 25-point-lower objective
VOL. 53, 2009
FIG. 2. Individual curve fits from NONMEM (dashed line), S-ADAPT (dotted line), and NPAG (continuous line) overlaid on observations
(markers).
function than the same absorption model with one disposition
compartment. As the latter model showed precise curve fits
and an excellent predictive performance, we chose the simpler
model as the final model.
The individual curve fits for the semiphysiological model
(Fig. 1) were excellent in all three programs (Fig. 2). The
model was flexible enough to fit profiles with sharp peaks,
plateau-like peaks, and dual peaks. No estimation algorithm
(program) provided the best fit for every subject. The linear
regression plot of individual fitted versus observed concentra-
tions had a slope of 1.007 and an intercept of 0.014 mg/liter
in NONMEM (r 0.9941), a slope of 1.011 and an intercept of
0.011 mg/liter in S-ADAPT (r 0.9928), and a slope of 1.003
and an intercept of 0.011 mg/liter in NPAG (r 0.9935).
The final estimates (Table 2 and Table 3) were precise. The
relative standard errors were 31% or less for all population
means (except for Km, 70% in NONMEM and 39% in S-
ADAPT) and 41% or less for all BSV estimates. The estimates
for apparent clearance and volume of distribution were similar
for all three programs. For the absorption parameters, the
differences were more apparent. The low Km/dose value
(mean, 0.433%) from NONMEM indicated that the release
from the stomach was estimated to be essentially a zero-order
process and that Vmax was inhibited in some subjects and stim-
ulated in others, as indicated by the negative or positive indi-
vidual Emax value.
In S-ADAPT, the release from the stomach to the intestine
had partial first-order and zero-order properties, as indicated
by the estimate of 42.6% for Km/dose. This rate of release was
POPULATION PK AND PD OF CEFUROXIME AXETIL 3465
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more notably stimulated, since the median (90th percentile) of
individual Emax values was 1.82 (5.55). NPAG estimated the
release from the stomach to the intestine primarily as a first-
order process (Km/dose, 343%), and stimulation of gastric
emptying was more pronounced than for S-ADAPT. The mean
TC50 values for the rate of gastric emptying after a standard-
ized breakfast were 1.61 h in NONMEM and S-ADAPT and
2.08 h in NPAG. Individual TC50 estimates were variable (Ta-
ble 2).
The VPCs (Fig. 3) indicated that the nonparametric simu-
lation based on the support points from NPAG yielded the
closest match between predicted and observed concentrations.
This was expected, since this simulation is based on the non-
parametric distribution of PK parameters that yielded precise
and unbiased fits for all 24 concentration-time profiles. The
parametric simulations based on the estimates from S-ADAPT
and NPAG matched the median and 10th to 90th percentiles
for the observations more closely between approximately 1 and
4 h than those based on NONMEM (Fig. 3). For the three
parametric simulations, S-ADAPT yielded the best represen-
tation of the observations during the terminal phase, followed
by NONMEM. The predicted variability was slightly too wide
during the terminal phase for the parametric simulation (Fig.
3) using the variance-covariance matrix derived from the sup-
port point matrix in NPAG.
As the VPCs showed that the nonparametric simulation
based on NPAG and the parametric simulation based on S-
ADAPT had the best predictive performance, breakpoints for
MCS are reported for these two models. The breakpoints for
 3466
TABLE 2. Population PK parameters for 250 mg oral cefuroxime given as cefuroxime axetil after a breakfast with a significant amount of fat
Value for:

NONMEM S-ADAPT NPAG

Parameter Symbol
Population Median (1090 percentile) Population Median (1090 percentile) Population Median (1090 percentile)
mean (% SEi) of individual estimates mean (% SEi) of individual estimates mean (% SEi) of individual estimates

Fixed effects
Apparent clearance (liters/h) CL/F 23.0 (8.1) 21.7 (16.827.9) 21.7 (4.1) 21.5 (17.127.8) 21.8c 21.8 (17.028.3)
BULITTA ET AL.

Apparent vol of distribution V/F 40.7 (6.3) 39.7 (28.847.6) 38.7 (4.1) 40.2 (30.445.8) 34.8 35.6 (25.548.0)
(liters)
Maximum rate of release from Vmax 0 /dose 0.381j (12)a 0.308 (0.2000.471) 0.505 j (22)a 0.418 (0.1641.48) 1.53a, j 1.35 (0.5002.66)
stomach to intestine at time
zero divided by dose (1/h)
Fraction of dose associated with Km/dose 0.433 (70)a 0.488 (0.1803.09) 42.6 (39)a 38.1 (4.70478) 343a 363 (193498)
50% of Vmax 0 (%)
Fastest half-life of gastric Ln(2)/Vmax 0 Km 0.534 (0.2706.36) 30.4 (13.0120) 104 (49.3155)
release, if fraction of dose in
stomach is Km/dose (min)
Absorption half-life from Tabsf 9.00 (29) 14.2 (3.4830.9) 9.34 (15) 9.20 (4.7016.2) 16.9 17.5 (4.0032.2)
intestine to central
compartment (min)
Time past meal at which Vmax TC50 1.61 (14) 2.06 (1.093.26) 1.61 (20) 1.53 (0.6195.05) 2.08 2.33 (1.145.31)
changed by 50% (h)
c
Maximum fractional change on Lg_Emax 3.59 (8.9) 3.14 (4.15 to 1.79) 0.762 (31) 0.937 (1.96 to 0.641) 0.515 0.50 (3.44 to 4.95)
transformed scale
Maximum fractional change Emax 0.582 (0.845 to 0.426) 1.82 (0.2425.55) 2.78 (0.582 to 8.93)
Hill coefficient 10g 10g 10g

Random effectsb
BSV(CL/F) 0.202b (18)h 0.198b (31)h 0.193e
BSV(V/F) 0.201 (16) 0.183 (32) 0.258
BSV(Vmax 0 /dose) 0.401 (22) 0.900 (30) 0.518
BSV(Km /dose) 1.23 (37) 1.80 (27) 0.403
BSV(Tabs) 0.867 (23) 0.600 (41) 0.634
BSV(TC50) 0.536 (25) 0.946 (31) 0.580
BSV(Lg_Emax) 1.09d (30) 0.990d (29) 3.03d
Proportional residual error 0.0754 (15) 0.0851 (5.5) 0.0620
Additive residual error (mg/liter) 0.0065 (24) 0.0029 (48) 0.0062
a
Vmax 0 and Km were estimated and are reported as fractions of the cefuroxime dose. This assumes that the rate of drug release from the stomach is primarily determined by the meal and not by the amount of cefuroxime
axetil. This assumption yields a linear increase in peak concentrations and no change in time to peak with dose, which is consistent with literature data.
b
These estimates for random effects represent the apparent coefficient of variation for the BSV. All variability estimates are reported as square roots of the estimated variance, since this square root is an approximation
of the coefficient of variation of a normal distribution on natural logarithmic scale.
c
For NPAG, the medians of the support point matrix are provided. For Lg_Emax, the arithmetic mean is reported, since the distribution of Lg_Emax was more symmetric and since this choice for Lg_Emax yielded a
better predictive performance in the VPC.
d
The variability estimate for Lg_Emax is reported as the SD on the transformed scale.
e
Estimates are coefficients of variation calculated based on the means SD of results from the support point matrix.
f
The corresponding rate constant kabs (in liters/h) is calculated as ln(2)/(Tabs/60).
g
The Hill coefficient was initially estimated, and estimates ranged between 10 and 15. To improve model stability, the Hill coefficient was subsequently fixed at 10. This had no notable effect on the curve fits and
the objective function.
h
The value in parentheses represents the uncertainty of the respective BSV estimate and is the relative standard error of the estimated variance (reported as %).
i
Standard errors are derived from a nonparametric bootstrap for NONMEM and are asymptotic standard errors for S-ADAPT.
j
This estimate represents the maximum fraction of stomach content that can be released into the intestine per hour. This maximum fraction can change over time as defined in the model.
ANTIMICROB. AGENTS CHEMOTHER.

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VOL. 53, 2009 POPULATION PK AND PD OF CEFUROXIME AXETIL 3467

TABLE 3. Variance-covariance matrix for the final population 0.375 mg/liter for 250 mg q8h, 0.188 mg/liter for 500 mg q12h,
PK model in S-ADAPTa and 0.75 mg/liter for 500 mg q8h). Additional simulations with
Parameter CL/F V/F Vmax 0/dose Km/dose Tabs TC50 Lg_Emax a hypothetical higher rate of absorption showed that the
PK-PD MIC breakpoints were lower if the rate of absorption
CL/F 0.0393
V/F 0.0326 0.0333 was faster. The decrease in breakpoints was most pronounced
Vmax 0/dose 0.1143 0.0877 0.8100 for the 65% fTMIC target and q12h dosing.
Km/dose 0.2693 0.2066 1.5925 3.2560
Tabs 0.0083 0.0142 0.1036 0.1640 0.3604 High PTA expectation values (97.8% for the 40% fTMIC
TC50 0.0931 0.0389 0.5324 1.0200 0.0459 0.8945 target) were achieved by all three dosage regimens shown in
Lg_Emax 0.1530 0.1131 0.5702 1.1824 0.0414 0.8197 0.9793
Table 4 for S. pyogenes, penicillin-susceptible S. pneumoniae,
a
V/F, apparent volume of distribution in the central compartment. See Table N. gonorrhoeae, and N. meningitidis (results not shown for the
2 for explanations of other parameters.
latter two pathogens). High (90%) PTA expectation values

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the other two simulation models were within one 1.5-fold di-
lution. The PTA-versus-MIC profiles were similar for these
two models (Fig. 4). For the bacteriostasis target fTMIC of
40%, the PK-PD MIC breakpoints in NPAG and S-ADAPT
were 0.5 and 0.375 mg/liter, respectively, for 250 mg q12h and
0.5 and 0.5 mg/liter, respectively, for 250 mg q8h. As these PK
models are linear with dose, 500 mg q12h achieved breakpoints
of 1 and 0.75 mg/liter and 500 mg q8h achieved breakpoints of
1 and 1 mg/liter in NPAG and S-ADAPT, respectively, for the
40% fTMIC target. For the near-maximal-killing target
fTMIC of 65%, the PK-PD MIC breakpoints for S-ADAPT
and NPAG were identical (0.094 mg/liter for 250 mg q12h,
were achieved for some but not all MIC distributions for S.
pneumoniae. The PTA expectation values were notably lower
for penicillin-intermediate S. pneumoniae, H. influenzae, M.
catarrhalis, S. aureus, and K. pneumoniae (results not shown for
the latter two pathogens).
DISCUSSION
Cefuroxime axetil has been used widely for treatment of
community-acquired upper and lower respiratory tract infec-
tions (including community-acquired pneumonia) (45) that are
often caused by S. pneumoniae, H. influenzae, M. catarrhalis,
and S. pyogenes. The reported MIC90s of cefuroxime against H.

FIG. 3. VPC for a single oral dose of 250 mg cefuroxime as cefuroxime axetil after a breakfast with a significant amount of fat for the final model
in each program. The continuous lines represent the 10th, 50th, and 90th percentiles for the simulated concentrations, the broken lines represent
the same percentiles for the observations, and the markers show the observations. Ideally, the continuous and corresponding broken lines should
fall onto each other. The insets show the terminal phase on a semilogarithmic scale.
3468 BULITTA ET AL.
FIG. 4. PTA-versus-MIC profiles for the PK-PD target fTMICs of
40% (top) and 65% (bottom) for the nonparametric MCS based
on NPAG (continuous lines) and the parametric MCS based on S-
ADAPT (broken lines).
influenzae and M. catarrhalis are often 2 or 4 mg/liter (41, 45).
Whereas most isolates would be deemed susceptible by the
CLSI breakpoint of 4 mg/liter for those pathogens, a signif-
icant number of isolates would be considered resistant accord-
ing to the BSAC and DIN susceptibility breakpoint of 1
mg/liter. To evaluate which breakpoint is in better agreement
with the predicted PK-PD MIC breakpoint, we applied para-
metric and nonparametric population PK modeling and MCS
for cefuroxime axetil.
The fTMIC best predicts the clinical and microbiological suc-
cess for cephalosporins. As the prolonged absorption phase of
cefuroxime axetil has a notable influence on the fTMIC values, it
was critical to develop a population PK model that adequately
captures the rates of absorption and BSVs that were observed in
our studies and in the literature. We intensively qualified the
predictive performance of our population PK model to ensure
that the model-predicted PK-PD MIC breakpoints are sound. An
8-fold increase (from 125 to 1,000 mg) in the oral cefuroxime
axetil dose after a meal causes a 7.5-fold increase in the area
under the curve and a 6.5-fold increase in peak concentrations
(20) and causes no systematically altered time of peak concentra-
tion (Tmax) (20). Data from rats suggest a saturable component
for the rate of absorption (4244).
We found a range of complex absorption patterns in healthy
volunteers (Fig. 2). Models with first-order or zero-order ab-
sorption with or without a lag time can describe the dose
proportionality in area under the curve and peak concentration
(20) but cannot describe a mixed-order rate of absorption and
the complex absorption profiles observed in our study. A
mixed-order absorption model with a lag time could describe
the plasma concentration time profiles of cefuroxime axetil at
ANTIMICROB. AGENTS CHEMOTHER.
one dose level (results not shown). However, such a mixed-
order absorption model would predict a notable increase in
Tmax with cefuroxime doses. This is in disagreement with the
data reported by Finn et al. (20). A mixed-order absorption
model cannot describe profiles with a dual peak.
Food increases the extent of bioavailability of cefuroxime
axetil from 36% in fasting subjects to 52% after a meal (20).
Similar results were found by Williams and Harding (54). In
both studies (20, 54), Tmax is prolonged by approximately 0.6 to
0.7 h for administration with food. Potential reasons for the
increased bioavailability and slightly longer Tmax observed un-
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der fed conditions include a more complete dissolution of
cefuroxime axetil due to a longer residence time in the stomach
and due to bile acid secretion stimulated by the presence of
lipids in the intestine (36, 50).
The proposed absorption model (Fig. 1) is in agreement with
the observations of literature studies for various dose levels of
cefuroxime axetil (20, 54). One limitation of our study is that
we had data only for 250 mg oral cefuroxime. Therefore, our
simulation results for 500 mg oral cefuroxime q12h should be
interpreted conservatively. The saturable rate of absorption is
described by a mixed-order release of drug from the stomach
to the intestine that is primarily saturated due to the presence
of food and not due to the cefuroxime axetil dose. In our
model, Vmax and Km are expressed as fractions of dose, and this
causes Tmax to be independent of dose. The second peak in
some profiles was described by an increase in the rate of gastric
release over time.
This semiphysiological model proved to be robust (Table 2)
and to yield excellent individual curve fits (Fig. 2) for all three
population PK algorithms and programs. This absorption
model was able to capture relevant features of complex oral
absorption profiles (24, 32, 53) which showed that the rate of
gastric emptying is important for the absorption of amoxicillin
(amoxicilline) and clavulanic acid (53).
Estimation of a full variance-covariance matrix and its use
during simulations yielded the best predictive performance,
caused no instability during estimation, and did not prolong
run times in S-ADAPT and NPAG. This saves modeling time,
since there are fewer decisions about the choice of the param-
eter variability model in S-ADAPT and NPAG than in
NONMEM. NPAG does not directly estimate the variance-
covariance matrix but always derives this full matrix from the
estimated support points. Estimating a full variance-covariance
matrix in NONMEM tended to cause model instability (i.e.,
unsuccessful termination messages and the inability of
NONMEM to obtain asymptotic standard errors) and notably
increased estimation times in NONMEM.
The most important difference between the parametric and
nonparametric approaches is that the former describes BSV by
a parametric, multivariate distribution (often a multivariate
log-normal distribution). In contrast, nonparametric methods
use a discrete set of support points to exactly store the BSV
and correlation structure of all estimated PK parameters in the
studied patient population. In the simplest case, each support
point essentially represents a complete set of PK parameters
for one patient and has a probability of 1 divided by the
number of subjects.
As the variability of individual PK parameter estimates in
the studied subject population is exactly represented by the
VOL. 53, 2009 POPULATION PK AND PD OF CEFUROXIME AXETIL 3469

TABLE 4. PTA expectation values for various cefuroxime axetil dosage regimens and PK-PD targets for the parametric
MCS based on S-ADAPT
PTA expectation value (%) for indicated PK-PD target dosage regimen

fTMIC 40% fTMIC 65%

Pathogen, source, and yr (no. of isolates)a Source or reference
250 mg 250 mg 500 mg 250 mg 250 mg 500 mg
q12h q8h q8h q12h q8h q8h

S. pyogenes
United States and Canada, 1997-1999 (119) 25 99.2 99.2 99.2 98.9 99.2 99.2
Germany, 2002 (340) 7 99.6 99.8 100 99.3 99.6 99.9
Europe, 1997-1999 (662) 26 98.9 99.3 99.6 96.7 98.9 99.4

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S. pneumoniae
United States and Canada, 1997-1999 (417) 25 65.9 67.6 70.2 56.4 65.6 68.1
United Kingdom, 2002-2003 (519) 38 94.4 95.0 96.2 90.6 94.2 95.2
Germany, 2002 (331) 7 97.3 98.0 98.2 93.4 97.0 98.0
Europe, 1997-1999 (2,018) 26 71.5 74.1 77.8 63.2 70.8 74.7

PSSP
United States and Canada, 1997-1999 (249) 25 97.8 98.5 99.3 91.4 97.6 98.6
Global, 1997-2000 (2,102) 6 98.2 99.0 99.6 92.7 98.0 99.2
Europe, 1997-1999 (1,274) 26 98.4 99.1 99.6 93.5 98.2 99.2

PISP
United States and Canada, 1997-1999 (70) 25 44.5 52.5 65.1 10.9 43.4 55.0
Global, 1997-2000 (1,024) 6 46.0 53.9 64.4 19.9 44.0 55.7
Europe, 1997-1999 (458) 26 39.9 48.8 60.8 18.0 37.8 50.9

H. influenzae
United States and Canada, 1997-1999 (300) 25 18.5 45.3 83.8 1.7 16.0 53.4
Canada, 2001-2002 (1,350) 55 19.3 44.4 81.6 4.8 17.3 52.2
United Kingdom, 2002-2003 (581) 38 41.1 67.6 88.8 3.9 33.7 72.4
Germany, 2002 (300) 7 72.4 91.6 98.1 13.2 64.7 93.6
EUCAST (66,947) EUCAST MIC 41.5 72.7 99.1 4.9 34.9 79.3
distribution websiteb

M. catarrhalis
United States and Canada, 1997-1999 (231) 25 26.2 49.5 82.5 3.6 22.7 56.0
United Kingdom, 2002-2003 (269) 38 35.1 63.0 93.0 3.6 30.0 69.7
Germany, 2002 (308) 7 11.8 35.5 77.4 1.5 10.5 43.6
a
PSSP, penicillin-susceptible S. pneumoniae; PISP, penicillin-intermediate S. pneumoniae.
b
Available at http://www.eucast.org/mic_distributions_of_wild_type_microorganisms/ (last accessed on 20 December 2008).

set of support points, it was expected that the nonparametric
VPC had the best predictive performance (Fig. 3). The para-
metric VPC using estimates from S-ADAPT had the best pre-
dictive performance among the parametric VPCs. We reported
the results from a parametric MCS in S-ADAPT with 10,000
virtual patients and from a nonparametric MCS in NPAG. As
every support point had the same probability for this study with
frequent sampling, the latter MCS was identical to simulation
from the individual PK parameter estimates of the 24 subjects.
The PTA-versus-MIC profiles from S-ADAPT and NPAG
were similar (Fig. 4). For 250 mg oral cefuroxime q12h or q8h,
the PK-PD MIC breakpoints fell between 0.375 and 0.5 mg/
liter for the bacteriostasis target fTMIC of 40% but were
approximately fourfold lower (0.094 mg/liter) for dosing of 250
mg q12h and the near-maximal-killing target fTMIC of 65%.
Dosing of 250 mg or 500 mg q8h increased the latter break-
points to 0.375 mg/liter or 0.75 mg/liter, respectively. Koeth et
al. (31) determined a PK-PD MIC breakpoint of 1 mg/liter
for susceptibility for standard cefuroxime dosage regimens
based on an fTMIC of 40 to 50%. This higher breakpoint is
expected, since Koeth et al. (31) used average PK parameters
for simulation and did not include BSV.
We did not manually increase the BSV in clearance and
volume of distribution to mirror the higher variability in criti-
cally ill patients, as the relatively low PK-PD MIC breakpoints
for oral cefuroxime do not support treatment of critically ill
patients. A higher variability in PK parameters and lower av-
erage extent of bioavailability after intake of cefuroxime in the
fasting state (20, 54) are expected to result in lower PK-PD
MIC breakpoints than those reported here. As the sample size
of 24 subjects probably did not allow us to obtain precise
estimates of the BSV in the whole patient population, the
results of our MCS should be interpreted conservatively. The
probability of clinical success of the simulated cefuroxime ax-
etil dosage regimens will ultimately depend on the MIC distri-
bution of the pathogen(s) of interest in the local hospital.
Dosing at 250 mg cefuroxime q8h instead of q12h had only a
small benefit for S. pyogenes and penicillin-susceptible S. pneu-
moniae, since 250 mg q12h achieved high PTA expectation
values, especially for the bacteriostasis target (Table 4).
Administering cefuroxime axetil q8h yielded notably higher
PTA expectation values for some but not all MIC distributions
of H. influenzae and M. catarrhalis. Although 500 mg oral
cefuroxime q8h is above the typically recommended oral cefu-
3470 BULITTA ET AL.
roxime dose, parenteral doses of up to 6,000 mg split into four
daily doses are recommended for severe infections.
To put the results of our MCS into a clinical perspective, we
compared our PTA expectation values to the microbiological
and clinical outcomes in clinical studies. Clinical data for chil-
dren with pneumococcal acute otitis media suggest a break-
point of about 0.5 mg/liter for oral cefuroxime (15). Shah et al.
(47) studied hospitalized patients and outpatients in 14 coun-
tries in Europe, Africa, and South America with acute exacer-
bation of chronic bronchitis (AECB) and found a 60% bacte-
riological overall cure rate for 250 mg oral cefuroxime given
twice daily (BID). This cure rate is comparable to the placebo
response rate for AECB (30, 46), depending on the severity of
disease. Interestingly, 56% (22 of 39) of the H. influenzae
isolates were eradicated. Using per-protocol and intention-to-
treat analyses, the authors reported clinical cure rates of 66%
and 61%, respectively, at the clinical endpoint (5 to 14 days
posttreatment) and of 53% and 39%, respectively, at the fol-
low-up 3 to 4 weeks posttreatment. Although the authors did
not report the MICs in those patients, the failures for the
treatment of H. influenzae show a suboptimal effectiveness of
oral cefuroxime against this pathogen.
Chodosh et al. (10) found a significantly lower microbiolog-
ical eradication rate for 500 mg oral cefuroxime BID (82%)
versus 500 mg oral ciprofloxacin BID (96%) in an outpatient
trial with AECB patients. Cefuroxime eradicated S. pneu-
moniae in 100% of the cases (13/13) but had eradication rates
of only 76% (19/25) for M. catarrhalis and 86% (19/22) for H.
influenzae. In an outpatient trial with AECB patients, de Abate
et al. (16) found a clinical cure rate of 77% for 250 mg oral
cefuroxime BID, which was significantly lower than the clinical
cure rate of 89% for 400 mg gatifloxacin once daily. The mi-
crobiological eradication rates were 77% for cefuroxime and
90% for gatifloxacin.
A trial using patients with community-acquired pneumonia
(19) showed a significantly lower rate of microbiological erad-
ication of H. influenzae for combinations of intravenous ceftri-
axone (1 to 2 g once daily or BID) and/or oral cefuroxime
axetil (500 mg BID) than for intravenous and/or oral levofloxa-
cin (500 mg once daily). The former regimen had an eradica-
tion rate of 79% and the latter 100%. Upchurch et al. (49)
found a clinical cure rate of 74.5% for treatment of acute
bacterial sinusitis with 250 mg oral cefuroxime for 10 days but
did not document the bacterial etiology. Alvarez-Sala et al. (1)
found a clinical success rate of approximately 82% for patients
with H. influenzae and S. pneumoniae for 250 mg oral cefu-
roxime q12h.
In conclusion, we developed a semiphysiological population
PK model for oral cefuroxime which provided precise and
unbiased individual curve fits for complex absorption profiles
and had an excellent predictive performance. The nonpara-
metric VPC based on NPAG showed a better predictive per-
formance than the best parametric VPC in S-ADAPT. The
PK-PD MIC breakpoints were 0.375 to 0.5 mg/liter for 250 mg
oral cefuroxime q12h and 0.5 mg/liter for 250 mg oral cefu-
roxime q8h for the bacteriostasis target fTMIC of 40%.
Dosing at 250 mg cefuroxime q8h instead of q12h increased the
breakpoint for the near-maximal-killing target fTMIC of 65%
from 0.094 mg/liter to 0.375 mg/liter. These breakpoints were
(slightly) lower than the susceptibility breakpoint of 1 mg/
ANTIMICROB. AGENTS CHEMOTHER.
liter provided by the BSAC and DIN, whereas the CLSI break-
point of 4 mg/liter for most pathogens is higher than the
PK-PD MIC breakpoints predicted by MCS in this study. Oral
cefuroxime (250 mg q12h or q8h) achieved high PTA expec-
tation values for S. pyogenes (96.7%) and penicillin-suscep-
tible S. pneumoniae (91.4%) but notably lower PTA expec-
tation values for M. catarrhalis, penicillin-intermediate S.
pneumoniae, and H. influenzae for most studied MIC distribu-
tions for various countries. Administering 250 mg oral cefu-
roxime q8h instead of q12h was most beneficial for the near-
maximal-killing target for MICs between 0.094 and 0.375 mg/
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liter. Future clinical studies that assess the MIC of the
causative pathogen are warranted to validate these predictions
for the clinical and microbiological success for q12h and q8h
cefuroxime axetil dosage regimens.
ACKNOWLEDGMENT
We thank George Drusano for fruitful discussions about this project.
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