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Estimation of Cefuroxime Dosage Using Pharmacodynamic Targets, MIC Distributions, and

Minimization of a Risk Function
Anders Viberg, Otto Cars, Mats O. Karlsson and Siv Jönsson
J. Clin. Pharmacol. 2008; 48; 1270
DOI: 10.1177/0091270008320923

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 Estimation of Cefuroxime Dosage Using
Pharmacodynamic Targets, MIC Distributions,
and Minimization of a Risk Function
Anders Viberg, PhD, Otto Cars, MD, PhD, Mats O. Karlsson, PhD, and Siv Jönsson, PhD
An approach for estimation of dosing strategies based on
data-derived models and assessment of the risk associated
with deviation from the treatment target is presented. The
work is illustrated by establishing a dosing strategy to be
used for a priori individualization on the basis of renal
function for the antibiotic cefuroxime. Treatment involved
exposing patients to concentrations above the minimum
inhibitory concentration (MIC) for 50% of the dosing inter-
val. The risk (penalty) function incorporated both devia-
tions from the target and the use of excess amount of drug.
Dosing strategies were estimated for a target population by
minimizing the risk function. The population was charac-
terized by a population pharmacokinetic model, and dis-
tributions of CLcr and body weight were reflective of the
target group. The estimated dosing strategies were assessed
W hen developing drug-dosing strategies, the
benefits and disadvantages of the treatment are
considered; that is, the desired effects have to be
weighed against the potential side effects. There is
usually an association between the magnitude of the
drug exposure and the effect; a too low dosage may
result in insufficient effect, and a too high dosage
may lead to adverse effects. By weighing the effects,
a target concentration associated with the greatest
probability of treatment success—sufficient clinical
effect with tolerable side effects—can be identified.
From the Division of Pharmacokinetics and Drug Therapy, Department of
Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
(Dr Viberg, Dr Karlsson, Dr Jönsson), and the Department of Medical
Sciences, Infectious Disease, Uppsala University Hospital, Uppsala,
Sweden (Dr Cars). Submitted for publication October 28, 2007; revised
version accepted May 15, 2008. Address for correspondence: Anders
Viberg, PhD, AstraZeneca R&D Södertälje, Clinical Pharmacology & DMPK,
SE-151 85 Södertälje, Sweden.; e-mail: anders.viberg@astrazeneca.com.
DOI: 10.1177/0091270008320923
1270 • J Clin Pharmacol 2008;48:1270-1281
by evaluating population distributions of (1) percentage of
dosing interval with concentrations above MIC, (2) time of
drug exposure below MIC, and (3) drug administered in
excess to reach the target. These distributions were gener-
ated using wild-type MIC distributions for Escherichia coli
and Streptococcus pneumoniae. The authors illustrate how
benefits and risks of drug treatment can be weighed quan-
titatively in decision-based risk functions and subse-
quently used in the estimation of drug dosing.
Keywords: Cefuroxime; dosing strategy; individualization;
MIC; risk function
Journal of Clinical Pharmacology, 2008;48:1270-1281
© 2008 the American College of Clinical Pharmacology
Subsequently, dosing strategies can aim at reaching
this target, and the need for individualization based
on a patient characteristic such as body weight, sex,
or a biomarker can also be assessed. In addition to
consideration of the drug effects/side effects, there
may be further aspects to take into account in the
establishment of a dosing strategy. For example,
using a higher dosing rate than necessary to achieve
a sufficient clinical response results in higher drug
costs, and for parenterally administered drugs, it
may also imply a logistic problem: the more frequent
dosing, the more time and personnel are required for
administration of the drug. Thus, when considered
to be of importance, the development of the dosing
strategy can also address such aspects.
With use of a pharmacokinetic (PK) and pharma-
codynamic (PD) model, it is possible to evaluate dif-
ferent dosing schedules by stochastic simulation
and, based on a predefined fulfillment criterion,
judge which of the different schedules is preferred.
However, simulating all possible dosing schedules
 ESTIMATION OF CEFUROXIME DOSAGE
to find the optimal dosing schedule is not feasible.
An alternative approach is to estimate an optimal
dosing strategy by minimizing a risk function
describing the seriousness of deviations from the tar-
get at which the treatment aims. This method has
been used when aiming at various PK and PD tar-
gets.1-7 Dosing strategies have, to our knowledge, not
been estimated for a drug in which the target is
dependent on the time the drug exposure is above a
threshold concentration. Furthermore, the approach
has not been used when target and risk function def-
initions take into account aspects other than the
desired effects and side effects, for example, cost of
treatment and amount of drug administered.
Cefuroxime, which is used as a model substance in
this study, is a second-generation cephalosporin that
has been used worldwide for more than 2 decades
against a variety of bacterial infections. In Sweden, it
is the most widely used parenteral antibiotic.
Following an intravenous dose of cefuroxime, the
plasma concentration exhibits 2-compartment phar-
macokinetics, with a total volume of distribution
ranging from 12 to 30 L and clearance proportional to
renal function (fraction excreted unchanged in urine
>90%) ranging from 0.8 to 9 L/h.8-14 Cefuroxime
shows activity against several pathogens (eg,
Escherichia coli and Streptococcus pneumoniae).
Beta-lactam antibiotics, like cefuroxime, show
time-dependent killing; that is, the longer time the
bacteria are exposed to unbound concentrations
above the minimum inhibitory concentration (MIC),
the better killing is achieved, and no proportional
increase in the killing effect is produced when con-
centrations are increased greater than 4 to 5 times
the MIC of the bacteria.15
However, in vivo as well as in vitro studies indi-
cate that it is not necessary to attain unbound con-
centrations above MIC for 100% of the dosing
interval for full effect; rather, 50% of the dosing
interval is suggested to be a breakpoint for full
effect during normal dosing.16-18 However, this PD
target is not unconditional; for example, when the
dosing interval is very long, the time that concen-
trations stay below the MIC might also become
long, and the bacteria may start to regrow. Severe
side effects following cefuroxime treatment rarely
occur, but a few have been reported, such as
skin rashes, sporadic reports of changes in hemato-
logical parameters, minor changes in liver transam-
inases, and reversible encephalopathy.19,20 Use
of cephalosporins might also result in disturbances
in the gut flora (eg, selection of Clostridium
difficile).21 Although the therapeutic interval for
cefuroxime appears to be wide, dose individualization
QUANTITATIVE CLINICAL PHARMACOLOGY
Table I Recommended Dosing Strategy for
Cefuroxime at Uppsala University Hospital
Clcr, mL/min Dose, mg Dosing Interval, h
<20 750 24
20-40 750 12
40-80 750 8
>80 1500 8
is suggested on the basis of renal function.22
The recommended dosing strategy at Uppsala
University Hospital involves 4 dosing categories, as
given in Table I.
The main aim of this study was to illustrate the
approach of optimizing dosing strategies based on
data-based models and decision-based risk func-
tions. Minimization of a multidimensional risk func-
tion is introduced as a feasible approach when
estimating a dosing strategy in which the target is a
combination of aspects weighed together, here the
time of drug exposure above a threshold concentra-
tion and the dose administered in excess to reach
the efficacy target. The work was illustrated by
establishing a dosing strategy to be used for a priori
individualization on the basis of renal function for
the antibiotic cefuroxime.
MATERIALS AND METHODS
For cefuroxime, the number of dose sizes available is
limited. Therefore, the dosing strategies estimated
comprise a discrete number of dosing categories;
that is, different dose rates are assigned to subpopu-
lations of the treated population. The treated popu-
lation is then categorized in the dosing strategy
using cutoff values of the patient characteristic used
for individualization.
The methodology used for estimation of dosing
strategies has been described previously4,5 and
involves several foundations: (1) a population PK
model and a description of covariate distributions in
the target population, (2) the definition of the aim
with treatment in terms of target and risk function,
(3) the estimation procedures including constraints
involved, and (4) an assessment of estimated dosing
strategies. This section will describe the issues nec-
essary to consider on an individual basis.
Description of the Target Population
This investigation was aimed at establishing a dosing
strategy for an adult population with bacterial infec-
tion treated with cefuroxime. A previously developed
1271
 VIBERG ET AL

Table II Population Parameter Estimates (% Relative Standard Error) in the

Modela Using Creatinine Clearance as a Renal Function Biomarker
Covariate Effectsa

Parameter Estimate IIV, % IOV, % CLcr, %/mL/min WT, %/kg

Clearance, L/h 5.49 (3.2) 30 (25) 17 (46) 1.96 (3.4) —

Central volume of distribution, L 11.1 (5.2) 18 (53) — — 1.13 (23)
Peripheral volume of distribution, L 5.09 (9.8) 46 (37) — — —
Intercompartmental clearance, L/h 3.96 (24) — — — —
Proportional residual error, % 14.9 (14) — — — —
CLcr, creatinine clearance; IIV, interindividual variability; IOV, interoccasion variability; WT, body weight.
a. In the final population model, clearance and central volume of distribution are implemented as
Clearance (L/h) = 5.49 • (1 + 0.0196 • (CLcr – 51.6)) and
Central volume of distribution (L) =11.1 • (1 + 0.0113 • (WT – 74)).

Table III Demographic Description of Patient Definition of the Therapeutic Target

Population (n = 110) Used to Characterize
the Target Population
Serum
creatinine,
Age, y Weight, kg μmol/L
Median 77 69 94
SD 16 13 57
Range 17-99 47-113 52-377
population PK model based on 97 cefuroxime-treated
patients with creatinine clearance ranging from 6.5 to
115 mL/min was used for the description of the PK
rate of cefuroxime in the target population.23 In this
model, Cystatin C was a covariate for clearance, but
for the purpose of this dose estimation, Cystatin C
was substituted with creatinine clearance (CLcr) cal-
culated by the Cockcroft and Gault formulae,24 and
new parameter estimates were estimated (Table II).
Based on empirical covariate distributions (body
weight and CLcr) descriptive of the target population
and the modified PK model, individual PK estimates
for one large population (N = 5000) were simulated to
be used during the estimation of dosing strategies.
The PK parameters were constrained within ±3 stan-
dard deviations of the unexplained interindividual
variability about the expected values based on CLcr
for CL and WT for V. Data for the empirical covariate
distributions of body weight and CLcr were obtained
from 110 consecutively registered cefuroxime-treated
hospitalized adult patients. The characteristics of the
distributions from these patients are described in
Table III.
The aim with any drug treatment is to recommend a
dosing strategy that will result in a positive benefit-
risk balance. In this investigation, the treatment tar-
get was a combination of exposing patients to
CLcr, mL/min
cefuroxime concentrations above MIC for at least
50 50% of the dosing interval (reaching sufficient effi-
26 cacy) and at the same time minimizing the amount
15-150 of drug administered in excess to reach the efficacy
target as a measure of nonbeneficial effects of treat-
ment. Thus, these 2 aspects were taken into account
in the target and risk function definition and are
described in detail in the following.
General model. The dose estimation was performed
using the underlying general model
Target = Predi + εi,
where Target is the aim of the treatment (here, a bal-
ance between time above MIC and the amount of
cefuroxime administered, described in more detail
below) and Predi is the individual prediction of Target
based on individual PK parameters, covariates, and the
estimated dosing strategy. Furthermore, εi is the indi-
vidual deviation from Target, that is, the deviations that
are minimized according to the risk function during
the estimation. The risk function describes how serious
the deviation (εi) from Target is considered, and exam-
ples are quadratic risk functions on the linear (RLIN) and
log (RLOG) scale described in the second equation. The
optimal dosing strategy was defined as the one mini-
mizing the deviations from Target overall according to
the defined risk function (ie, the dosing strategy that
minimized the risk function).

1272 • J Clin Pharmacol 2008;48:1270-1281

 ESTIMATION OF CEFUROXIME DOSAGE
N
RLIN = ∑ [Target − Predi]2
i=1
N Time below MIC = 6 h
RLOG = ∑ [ln(Target) − ln(Predi)] . 2 15
i=1
Target values. As stated, one part of the target (ie, the
aim of treatment from an efficacy point of view) was
to expose the individuals to concentrations above
MIC for at least 50% of the dosing interval; thus, the
target value was set to 50%. To calculate this value,
the MIC must be defined and is part of the definition
of the target. In this work, the MIC was set to a fixed
value during the estimation. The fixed MIC value
was chosen in relation to MIC distributions for 2 dif-
ferent species of bacteria representing typically
infecting pathogens, E coli and S pneumoniae. The
time during which cefuroxime concentrations were
above MIC (T>MIC) was calculated for each individual
during the minimization, as a function of the indi-
vidual simulated PK parameters, the fixed MIC
value, and the estimated dosing strategy. It was
assumed that cefuroxime bound to serum proteins is
inactive and that reported MIC values represent
unbound concentrations. Therefore, the target con-
centration was corrected for fraction unbound that
was assumed to be 65%.9,25 For each individual, the
percentage of the dosing interval with concentra-
tions above MIC (%T>MIC) was calculated as %T>MIC =
100 • T>MIC/estimated dosing interval.
The second part of the target, amount of drug
administered, was taken into account when the effi-
cacy target was reached, that is, when the individual
prediction of %T>MIC was greater than 50%. In that
situation, the target was switched to the relative
amount of drug administered in excess to reach
%T>MIC = 50% on an individual level (hereafter
called drug in excess), and this target was set to the
value 0, meaning that administration of a drug
amount resulting in %T>MIC = 50% yields no risk.
Drug in excess was obtained according to
Drug in excessi = ⎧ – − ——— ⎫
1 1 1
/ ——— ,
⎩ τ τ Dose,i ⎭ τ Dose,i
where τDose,i is the dosing interval resulting in %T>MIC =
50% for each dose size for each individual in the
simulated population and τ is the estimated dosing
interval. Accordingly, an estimated dosing interval
shorter than τDose,i would result in giving drug in
excess.
QUANTITATIVE CLINICAL PHARMACOLOGY
A B
20 Time below MIC = 4 h
20 Time below MIC = 4 h
Time below MIC = 6 h
Time below MIC = 8 h
Time below MIC = 10 h
15 Time below MIC = 8 h
Time below MIC = 10 h
Risk
Risk
10 10
5 5
0 0
0 25 50 0 1 2 3 4
%T>MIC Drug in excess
Figure 1. Graphical representation of the risk functions used in
the estimations: the solid black line (time below MIC = 4 hours)
represents RF1, and the other lines represent RF2. %T>MIC is the
fraction of the dosing interval to which an individual is exposed
above MIC, drug in excess is the relative amount of drug given in
excess to reach %T>MIC = 50%, and time below MIC is the hours of
concentration below MIC in each dosing interval.
Risk functions. In addition to describing the serious-
ness of a deviation from target, the risk function defi-
nitions also balance/weight the penalties resulting
from deviations in the 2 parts of the Target as follows.
It was assumed that exposure below target was worse
than giving too much drug. Therefore, the risk func-
tion was constructed so that predictions below the
efficacy target (ie, %T>MIC ≤ 50%) were penalized
according to a quadratic function on the log scale.
When %T>MIC > 50%, predictions with respect to drug
in excess were penalized by a quadratic function on a
linear scale. The 2 different penalties were weighed
so that %T>MIC = 25% gave the same penalty as the
administration of 100% drug in excess. The risk func-
tion (RF1) is described graphically in Figure 1.
An expanded risk function (RF2) was developed
for situations in which the target T>MIC = 50% is
reached but the estimated dosing interval becomes
very long (eg, 48 hours) for the subpopulations of
patients with low renal function. This may increase
the risk for regrowth of bacteria, as the time the
patient is exposed to concentrations below MIC is
considerable. Therefore, RF2 was constructed to
include an added quadratic penalty on the linear
scale when the individual was exposed to a concen-
tration below MIC for longer than 4 hours per dosing
interval. This penalty was weighted so that 6 hours
below MIC resulted in the same penalty as %T>MIC =
25% (Figure 1).
Estimation of the Dosing Strategy
The dosing strategies estimated for cefuroxime
assume intravenous bolus administration and that
1273

A B
Number of reported cases
40000
34000
28000
22000
16000
10000
0.125 0.25 0.5 1 2 4 8
Minimum inhibitory concentration (mg/L)
Figure 2. Wild-type MIC distributions of E coli (left) and S pneumoniae (right) obtained from the EUCAST database.
only a discrete number of dose sizes (250, 750, and
1500 mg) are available. A dosing strategy consists of
the dose size(s), the dosing interval(s), and the creati-
nine clearance cutoff values (CO) at which the dose
rate should be increased or decreased. In this study, a
series of dosing strategies individualized on the basis
of CLcr, composing up to 5 dosing categories, were
estimated. In the estimations, the dosing intervals and
the COs were the dosing aspects estimated, while the
dose sizes were fixed. For each dose size, dosing
strategies with 2, 3, and 4 categories were estimated
(corresponding to the estimation of 1, 2, and 3 COs).
Alternative dosing strategies were used when 2 dose
sizes were used in the same estimation. All dosing
strategies were estimated using the following fixed
MIC values: 0.25, 1, 8, and 16 mg/L. The dose size
was fixed to 250 or 750 mg for the 2 lower MIC val-
ues and to 750 or 1500 mg for the 2 higher MIC val-
ues. The estimation was a stepwise search in which
the COs were restricted to take on values that were
multiples of 10 mL/min CLcr values, as described
previously.5 For each stepwise search, the estimation
resulting in the lowest objective function value was
considered the best dosing strategy.
All estimations were performed for steady-state
conditions using NONMEM,26 although the estimations
1274 • J Clin Pharmacol 2008;48:1270-1281
VIBERG ET AL
9000
Number of reported cases
6000
3000
0
16 0.004 0.008 0.016 0.032 0.064 0.125
Minimum inhibitory concentration (mg/L)
do not require a nonlinear mixed-effects computer
program.
Assessment of Estimated Dosing Strategies
To assess whether an estimated dosing strategy was
sufficient and to compare dosing strategies, evalua-
tions related to the target definitions were performed
as follows. The distribution of %T>MIC and, when
estimated dosing intervals were long, the distribu-
tion of the time of drug exposure below MIC were
obtained for the simulated population to evaluate
the dosing strategies from the efficacy viewpoint.
Similarly, the distribution of drug in excess was cal-
culated to judge the nonbeneficial side of cefurox-
ime treatment. The distributions of these 3 variables
were calculated using wild-type MIC distributions
for 2 different species of bacteria representing typi-
cally infecting pathogens, E coli and S pneumoniae.
In the calculations, each individual in the simulated
population was randomly assigned 1 MIC value
from each of the MIC distributions. The wild-type
MIC distributions for E coli and S pneumoniae were
obtained from the EUCAST database27 based on
88 608 and 25 883 reported strains, respectively. The
MIC distributions are displayed in Figure 2.
 ESTIMATION OF CEFUROXIME DOSAGE

A B C
10 23% < 50 %T 77% > 0 Drug in excess 28% > 4 hours below MIC
>MIC 50 30

8 25
40

% of population
% of population
% of population

20
6 30
15
4 20
10

2 10 5

0 0 0
0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10 4 12 20 28 36 44
%T>MIC Drug in excess Hours below MIC

D E F
10 0.06% < 50 %T>MIC 100% > 0 Drug in excess 30 0.08% > 4 hours below MIC
50

8 25
40

% of population
% of population
% of population

20
6 30
15
4 20
10

2 10 5

0 0 0
0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10 4 12 20 28 36 44
%T>MIC Drug in excess Hours below MIC

Figure 3. Distributions of the fraction of time with concentration above MIC per dosing interval (%T>MIC), drug in excess to reach %T>MIC =
50%, and time below MIC per dosing interval assessed using the wild-type distribution of E coli (upper panel) and S pneumoniae (lower
panel), respectively, for the traditionally used dosing schedule (see Table I).

RESULTS with a dose many times higher than that needed to

reach the efficacy target.
Traditionally Used Dosing Schedule
Estimated Dosing Strategies: General Findings
The distributions of %T>MIC, the time of drug expo-
sure below MIC, and drug in excess for the tradi- Generally, increasing the fixed MIC value in the dosing
tionally used dosing schedule were assessed using strategy estimation resulted in shorter estimated
the 2 strains of bacteria and are presented in Figure 3. dosing intervals, given the same dose size. Furthermore,
As shown, the dosing schedule results in %T>MIC < the consequence of using the lower dose size com-
50% for 23% of the E coli infections but only 0.06% pared with the higher dose size was shorter dosing
of the treated S pneumoniae infections. In addition, intervals. Dosing strategies involving 2 different dose
all infections caused by S pneumoniae are treated sizes did in no case result in a significant benefit

QUANTITATIVE CLINICAL PHARMACOLOGY 1275

 VIBERG ET AL

compared with dosing strategies with only 1 dose

size. It was possible to estimate dosing schedules for A B
all tried settings, but it was a clear difference in the 10 15% < 50 %T>MIC 85% > 0 Drug in excess
assessment of the various strategies depending on 50

the wild-type MIC distribution used. Therefore, the 8

40

% of population

% of population
remaining part of the result section is organized with
6
respect to dosing strategies evaluated for each of the 30

2 distributions used in the assessment of the dosing 4 20

strategies.
2 10
Dosing Strategies Evaluated With
0 0
Respect to E coli Infections 0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10
%T>MIC Drug in excess
Using the fixed MIC value 8 mg/L and 750 mg in the
estimation resulted in a large proportion of individ- C D
uals exposed to %T>MIC < 50%. This proportion
diminished and the distribution of individuals 10 16% < 50 %T>MIC
50
84% > 0 Drug in excess
below target was shrunken toward the target when
8
the number of dosing categories was increased; that % of population
40

% of population
is, fewer individuals were exposed to very low 6 30
%T>MIC with an increasing number of COs (Figure 4).
Conversely, the proportion of individuals who were 4 20
given drug in excess increased when the proportion
2 10
of individuals below target decreased, that is, with
an increase in the number of COs (Figure 4). Using 0 0
0 10 20 30 40 50
the higher dose size (1500 mg) resulted in an even 0 1 2 3 4 5 6 7 8
Drug in excess
%T>MIC
larger proportion of individuals with %T>MIC < 50%
(results not shown).
When the fixed MIC value was increased to 16 E F
mg/L and the 750-mg dose size was used, good tar-
10 20% < 50 %T>MIC 80% > 0 Drug in excess
get attainment was obtained with respect to %T>MIC 50
< 50%, but the estimated dosing intervals were very 8
40
short for patients with good renal function (ie, ≤3
% of population

% of population

hours, results not shown). Using the 1500-mg dose 6 30

size resulted also in only a small proportion of the
4
individuals exposed to %T>MIC < 50%, and conse- 20

quently, a large proportion was exposed to drug in 2 10

excess (Figure 5). In accordance with the results for
MIC 8 mg/L, by increasing the number of COs, the 0
0 10 20 30 40 50
0
0 1 2 3 4 5 6 7 8 9 10
width of the distribution of %T>MIC and drug in %T>MIC Drug in excess
excess decreased. For all dosing strategies, and in
particular when using 4 dosing categories (3 COs),
Figure 4. Distributions of the fraction of time with concentra-
the dosing interval for the patients with best renal tion above MIC per dosing interval (%T>MIC) and drug in excess,
function was short (Table IV) but longer than for the assessed using the wild-type distribution of E coli for the dosing
750-mg dose size. strategies estimated using a fixed MIC value of 8 mg/L and a
dose size of 750 mg. Results are shown for a dosing strategy with
To achieve acceptable efficacy, one of the dosing 4 (upper panel), 3 (middle panel), and 2 (lower panel) dosing
strategies resulting from using 1500 mg and MIC 16 mg/L categories.
in the minimization should be chosen (Table IV).
When comparing efficacy and drug in excess among
the different dosing strategies, the benefits of an numbers (6 and 12 hours) when using 2 dosing cate-
increasing number of dosing categories is limited, gories and only estimating CO resulted in the same
and therefore 2 dosing categories would be considered CO (50 mL/min), and similar distributions of effi-
sufficient. Setting the dosing intervals to practical cacy and drug in excess were obtained.

1276 • J Clin Pharmacol 2008;48:1270-1281

 ESTIMATION OF CEFUROXIME DOSAGE

Table IV Estimated Dosing Strategies

A B With 2, 3, and 4 Dosing Categories, Respectively,
10
Using the Dose Size 1500 mg
4.0% < 50 %T >MIC 96% > 0 Drug in excess
50
2 Dosing Categories 3 Dosing Categories 4 Dosing Categories
8
40
% of population

% of population
CLcr, Dosing CLcr, Dosing CLcr, Dosing
6 30 mL/min Interval, h mL/min Interval, h mL/min Interval, h
4 20 ≤50 12.04 ≤30 17.61 ≤30 17.61
2
>50 5.28 30-80 9.51 30-50 9.50
10
>80 5.29 50-70 6.23
0 0 >70 4.19
0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10
%T>MIC Drug in excess Abbreviation: CLcr, creatinine clearance.
A fixed MIC value of 16 mg/L was used in the estimation.

C D

10 4.7% < 50 %T >MIC 95% > 0 Drug in excess 250 mg in the minimization, as shown in Table V. A
50
large proportion of individuals were exposed to T>MIC
8
40 < 50%, and, in addition, many of them were exposed
% of population

% of population

6
to concentrations below MIC for longer than 4 hours
30
(Figure 6), but only a few individuals exhibited high
4 20 values of drug in excess. However, when incorporat-
ing the risk of being below MIC for more than 4 hours
2 10 in the estimation (ie, using RF2 in the minimization),
0 0
the resulting dosing intervals were shorter (Table V),
0 10 20 30 40 50 0 1 2 3 4 5 6 the proportion of individuals below target and
Drug in excess
%T>MIC number of individuals with concentration below MIC
for more than 4 hours were considerably reduced, and
E F the number of individuals with exposure above target
increased (Figure 7).
10 6.4% < 50 %T>MIC
50 94% > 0 Drug in excess An overall assessment of efficacy (%T>MIC and the
8
risk of being below MIC for more than 4 hours) and
40
drug in excess resulted in only small benefits using
% of population

% of population

6 30 more than 2 dosing categories (results not shown).

4 20
2 10
0 0
0 10 20 30 40 50
%T>MIC
Figure 5. Distributions of the fraction of time with concentration
above MIC per dosing interval (%T>MIC) and drug in excess, assessed
using the wild-type distribution of E coli for the dosing strategies
estimated using a fixed MIC value of 16 mg/L and dose size of 1500
mg. Results are shown for a dosing strategy with 4 (upper panel), 3
(middle panel), and 2 dosing categories (lower panel).
Dosing Strategies Evaluated With
Respect to S pneumoniae Infections
Very long dosing intervals were estimated when using
the fixed MIC value of 0.25 mg/L and a dose size of
Hence, the estimated dosing strategy with 2 dosing
categories using RF2 was reestimated with the dosing
intervals fixed to 12 and 24 hours. This resulted in a
somewhat lower CO (30 mL/min), but similar effi-
cacy and drug in excess were obtained.
0 1 2 3 4 5 6 7 8 9 10
Drug in excess
DISCUSSION
This work illustrates how a dosing schedule for an
antibiotic drug, to be used for a specific target popu-
lation, can be developed by minimizing a multidi-
mensional risk function. Although cefuroxime was
used in this example, the methodology could in gen-
eral be applied for drugs used in any therapeutic
area and would be especially useful for drugs with a
narrow therapeutic index.
The estimation of the dosing schedule involves a
number of critical definitions. One of them is defin-
ing the aim of treatment, which is a prerequisite for

QUANTITATIVE CLINICAL PHARMACOLOGY 1277

 VIBERG ET AL

A B c
16% < 50 %T>MIC 84% > 0 Drug in excess 25 58% > 4 hours below MIC
10 60

8 50 20

% of population
% of population

% of population
40
6 15
30
4 10
20
2 5
10

0 0 0
0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10 4 12 20 28 36 44
%T>MIC Drug in excess Hours below MIC

Figure 6. Distributions of the fraction of time with concentration above MIC per dosing interval (%T>MIC), drug in excess, and time below
MIC per dosing interval assessed using the wild-type distribution of S pneumoniae for the dosing strategy estimated using a fixed MIC
value of 0.25 mg/L, dose size of 250 mg, and risk function 1. Results are shown for a dosing strategy with 2 dosing categories.

A B c

10 1.3% < 50 %T>MIC 99% > 0 Drug in excess 25 5.1% > 4 hours below MIC
50
8 20
% of population

% of population
% of population

40
6 15
30
4 10
20

2 10 5

0 0 0
01 02 03 04 05 0 0 1 2 3 4 5 6 7 8 9 10 4 12 20 28 36 44
Drug in excess Hours below MIC
%T>MIC

Figure 7. Distributions of the fraction of time with concentration above MIC per dosing interval (%T>MIC), drug in excess, and time below
MIC per dosing interval assessed using the wild-type distribution of S pneumoniae for the dosing strategy estimated using a fixed MIC
value of 0.25 mg/L, dose size of 250 mg, and risk function 2. Results are shown for a dosing strategy with 2 dosing categories.

1278 • J Clin Pharmacol 2008;48:1270-1281

 ESTIMATION OF CEFUROXIME DOSAGE
Table V Estimated Dosing Strategies Using a
Fixed MIC Value of 0.25 mg/L, Dose Size
of 250 mg, and Risk Function 1 (RF1) and
Risk Function 2 (RF2), Respectively
RF1 RF2
Clcr, Dosing Clcr, Dosing
mL/min Interval, h mL/min Interval, h
≤40 43.3 ≤40 19.35
>40 19.9 >40 11.6
Abbreviation: CLcr, creatinine clearance.
any method employed to establish a dosing strategy.
In a simple situation, dosing is to be calculated for
a single patient with known PK characteristics; set-
tlement of a value of the chosen target (eg, a steady-
state concentration of x units) and the appropriate
dosing for the individual (given known PK parame-
ters) can be calculated. In the approach presented
here, what is needed is not only specifying the
value of the target but also defining how seriously
to judge a deviation from the target expressed quan-
titatively in a risk function. From the efficacy per-
spective, we aimed in our estimations to establish a
dosing strategy resulting in %T>MIC = 50%, on the
basis that dosing where %T>MIC < 50% results in less
effective killing of bacteria and dosing where
%T>MIC > 50% does not increase the killing. In the
alternative risk function, we added consideration of
the duration of continuous time intervals below the
MIC. For cefuroxime, concentration-dependent tox-
icity is limited, and it can be argued that using a
high enough dosing strategy resulting in all
patients’ reaching the efficacy target would be
appropriate. However, from both an economical and
an ecological/resistance perspective, we also con-
sidered minimizing the amount of drug adminis-
tered in excess to reach the efficacy target. A major
difficulty in the construction of the risk function
was to weight the aspects against each other. The
choices made should preferably have a scientific
basis but will also contain value judgments, as
exemplified in this study. If dosing drug in excess
would have been considered worse than treating
below the efficacy target, the risk functions should
have been defined accordingly, and dosing strategies
with longer dosing intervals and/or lower dose sizes
would have been estimated in that situation. The
main purpose of this work was to illustrate the
approach of estimating optimal dosing strategies
QUANTITATIVE CLINICAL PHARMACOLOGY
based on data-based models and decision-based risk
functions.
On a macroscopic level, it is known that high con-
sumption of antibiotics leads to drug resistance. At
present, it is not known how the treatment should be
individualized to minimize the development of
antibiotic resistance. However, if (or rather when)
such knowledge is available, it would be possible to
include this information in the risk function defini-
tion. The risk of antibiotic resistance development
could then be weighed against drug effect and drug
toxicity when estimating the dosing strategy. Also,
when other types of PK/PD models28 are validated in
patients, it will be possible to use other target vari-
ables than %T>MIC and other risk functions to better
individualize the dosing.
During development of new antibiotics, there is
often a limited knowledge of the MIC distribution
for the population of pathogens that is intended to
be treated. To resemble a drug development situa-
tion, we therefore chose to use a fixed MIC value for
calculation of %T>MIC and T>MIC, rather than using the
available distribution of MIC values in the estima-
tion of the dosing strategies. If the distribution of
MIC values is not known at early stages in drug
development, it will be necessary to use a fixed MIC
value based on the higher values of MIC for the
species pathogen that is the target of the antibiotic
treatment. Fixing the MIC to a value not representa-
tive of the intended MIC population will of course
end up in a suboptimal dosing strategy. We
employed several MICs for each pathogen of interest
and evaluated the dosing strategies with the MIC
distributions. Using an MIC of 16 mg/L for E coli can
be considered as estimating a highest dose rate
required for the population. It is expected that the
dosing intervals estimated applying an E coli MIC
distribution would be longer compared with using a
fixed value of 16 mg/L as the average MIC is lower
in the distribution. The estimate will, however, also
be dependent on the shape of the MIC distribution.
However, to be able to calculate target attainment,
as we have defined it, it is necessary to have a repre-
sentative distribution of MIC values. In our example,
we used the wild-type distribution from EUCAST.
The number of reported strains in the database is very
high, and it is representative of the sensitivity of bac-
teria causing infection treated with cefuroxime in
Sweden. If treatment is intended for resistant species
not within the wild-type MIC distribution, it will be
necessary to use another distribution. If a representa-
tive MIC distribution does not exist, the target assess-
ment will have to be done according to deviations
1279
 VIBERG ET AL
from the target using the fixed MIC value and the
practicality of the dosing strategy.
When comparing different estimated dosing strate-
gies, it will be necessary, once again, to weigh the pros
and cons. The risk of suboptimal treatment has to be
compared with the risk of side effects and number of
dosing categories. A predefined criterion could be
chosen to evaluate whether a dosing strategy is suc-
cessful (ie, no more than X individuals should have
%T>MIC = Y%). Instead of using a predefined criterion,
we chose to look at the distributions of deviations
from target. This makes it possible to evaluate more
aspects of the dosing strategy. Not only the total
number of individuals below a specific target value
but also how the deviations are distributed can be con-
sidered. This might occur in a situation in which a
small number of extreme deviations have to be
weighed against a large number of small deviations
from the target. By comparing the different distribu-
tions, it is possible to evaluate how much is gained by
increasing the number of dosing categories. The fewer
dosing categories, the easier in clinical praxis, but still,
as many individuals as possible should have optimal
treatment. What also needs to be considered is the
practicality of the dosing intervals; that is, an integer
number of doses should be given on a daily basis.
By using 2 different MIC distributions for assess-
ment of target fulfillment, our results indicate that dif-
ferent dosing schedules could be used depending on
the infecting pathogens. If the species of the infecting
pathogen is known (and the distribution of MIC val-
ues it originates from) or, even better, if the MIC value
of the infecting pathogen is known, the dosing could
be individualized not only based on renal function
but also based on the sensitivity to the drug of the
infecting pathogen.
The assessment of the dosing strategies indicates that
the recommended dosing of cefuroxime (Table I) might
be too low for treatment of infections caused by E coli.
The estimated dosing interval considered to be suffi-
cient for the dosing strategy is much shorter than the
one presently used. However, reducing the dosing inter-
vals is impractical, and another option would be to con-
sider other antibiotic treatment. For infections caused
by S pneumoniae, our results indicate that a dosing
strategy comprising only 2 dosing categories with lower
dose rates than those used at present (Table I) would be
sufficient. In addition, the results indicate that an even
lower dose size than 250 mg could possibly be used
for infections caused by S pneumoniae and still suffi-
ciently reach the efficacy target as defined in this work.
Financial disclosure: None declared.
1280 • J Clin Pharmacol 2008;48:1270-1281
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