Perspective

Advances in paediatric
pharmacokinetics
Catherijne AJ Knibbe†, Elke HJ Krekels & Meindert Danhof
†
University of Leiden, Leiden/Amsterdam Center for Drug Research, Division of Pharmacology,
1. Introduction and relevance Leiden, The Netherlands and St. Antonius Hospital, Department of Clinical Pharmacy, PO Box
2. Pharmacokinetic model 2500, 3430 EM Nieuwegein, The Netherlands
development in the paediatric
Importance of the field: In recent years, interest in paediatric pharmaco-
population
kinetics has grown. Even though pharmacokinetic and pharmacodynamic
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Universite De Sherbrooke on 11/28/12

3. Conclusion
relations determine together the optimal drug dose, age-related changes in
4. Expert opinion pharmacokinetics have proven of utmost importance for optimising drug
dosing in children.
Areas covered in this review: Constraints in paediatric studies result in data
sets with specific characteristics requiring advanced analysis and validation
approaches which are discussed in conjunction with directions for
future research.
What the reader will gain: Advances have been made in the development of
descriptive paediatric pharmacokinetic models for specific drugs and age
ranges, and in the identification of analysis and diagnostic tools for paediatric
model building and evaluation, while sharing of data between academia and/
or industry has proven crucial for limiting additional burden in children. Even
For personal use only.

though progress is being made, currently none of the scaling approaches has
proven of universal value for extrapolations to other age ranges and/or other
drugs.
Take home message: The focus of future research should be on the develop-
ment of mechanistic and validated pharmacokinetic models for specific
elimination routes that have predictive and extrapolation potential, making
them of use in designing algorithms to derive first-time-in-child doses and
individualised dosing guidelines in paediatrics.

Keywords: maturation, paediatrics, pharmacokinetics, population PK modelling

Expert Opin. Drug Metab. Toxicol. (2011) 7(1):1-8

1. Introduction and relevance

In recent years, from both an academic and an industrial perspective, interest in pae-
diatric pharmacology has grown. Besides academic interest of clinical pharmacolo-
gists in paediatric pharmacokinetics, interest from an industry perspective has
been raised by legislation that has recently come into effect in both the US (Best
Pharmaceuticals for Children Act (2002), and Pediatric Research Equity Act
(2003)) and Europe (Pediatric Regulation (2007)). This legislation encourages or
even compels pharmaceutical companies to perform research in the whole paediatric
age-range before marketing. In contrast to the US, the EU has also assigned funds
for research in children for off-patent drugs (FP7 program) in order to get licensed
paediatric formulations with proper evidence-based dosing guidelines to the Euro-
pean market for drugs that are already marketed for adults. This has led to close
cooperation between small or medium sized enterprises and academic research
groups to get these Paediatric-Use Marketing Authorization products to the
EU market.
The reason for all these regulations and initiatives is that to date only a small
number of drugs used in children are licensed for this special group. A review

10.1517/17425255.2011.539201 © 2011 Informa UK, Ltd. ISSN 1742-5255 1

All rights reserved: reproduction in whole or in part not permitted
 Advances in paediatric pharmacokinetics
from 2005 showed that unlicensed and off-label drug pre-
scription in children ranged between 11 and 37% in commu-
nity settings and between 55 and 80% in neonatal wards [1].
Unlicensed paediatric dosing regimens are usually empirically
derived from, for instance, adult regimens and may vary
within and between countries leading to wide (linear) dosing
ranges for which there is no thorough scientific basis.
Similar to other patient populations, the optimal dose in
children is determined by both the pharmacokinetics and
pharmacodynamics. Currently in paediatric pharmacology,
structural knowledge on the influence of maturation on either
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Universite De Sherbrooke on 11/28/12
the pharmacokinetics or pharmacodynamics of drugs is scarce,
while research nowadays focuses predominantly on the
influence of age-related physiological changes on the pharma-
cokinetics of a drug. This is partially because validated phar-
macodynamic endpoints for the paediatric population are
currently still relatively scarce. Additionally, pharmacokinetic--
pharmacodynamic analyses are conventionally performed
sequentially, focussing on the pharmacodynamics only after
the pharmacokinetics are described. It is, however, important
to note that these pharmacodynamic studies are imperative
for the development of evidence-based dosing regimen in the
paediatric population also. There may, however, be a few
exceptions, for example, when it is reasonable to assume that
For personal use only.
the underlying disease mechanism and the concentration--effect
relationship are the same in adults and children. For this
purpose, the FDA has provided a decision tree (Figure 1) to
evaluate whether pharmacokinetic investigations alone suffice
for the adjustment of paediatric dose or whether additional
paediatric efficacy studies are required as well. In summary, to
both clinicians and industry, information on age-related
physiological changes in pharmacokinetics in children is of
utmost relevance, even though final decisions on the optimal
dose recommendations in children should be based on both
pharmacokinetics and pharmacodynamics in children.
2.Pharmacokinetic model development in
the paediatric population
2.1 Paediatric datasets
In general, paediatric datasets from prospective clinical trials
on drug pharmacokinetics are scarce, especially datasets that
cover the entire paediatric age-range. Moreover, in these data-
sets, both the number of children included per study and the
number of observations per child are usually small, while the
number and time points of observations per individual may
also differ. Part of these limitations can be overcome by the
use of published paediatric data or by sharing data between
academic groups and/or industry. This is not only important
for initial pharmacokinetic model building but also for con-
firming the external validity of the derived model by testing
the predictive performance of the model in other datasets of
patients in the same age-range. Unfortunately, sharing data
between academic and/or industry groups is often restricted
by non-harmonised data recording, presumed need for
2 Expert Opin. Drug Metab. Toxicol. (2011) 7(1)
additional permission of an Investigational Review Board,
propriety claims and/or conflicting interests. In any case,
data-sharing requires strict agreements with regard to
confidentiality, the exact purpose of the data-sharing and
the infrastructure for storing data in a secure environment.
In this respect, the open TCI initiative by the World Soci-
ety of Intravenous Anaesthesia is highly unique, with differ-
ent, fully anonymised datasets of propofol and remifentanil
concentrations and patient characteristics available on the
Internet [2]. Another important initiative, supported by the
Top Institute Pharma in The Netherlands, is the foundation
of the TI Pharma Mechanism-Based PK-PD Modelling Plat-
form which has established an infrastructure for sharing ano-
nymised data from both academia and international
pharmaceutical industry in a secure environment [3,4]. Within
the platform, there is a restricted access for authorised
investigators to these databases.
Another way to generate optimal datasets in children would
be to call for multidisciplinary teams including specialists in
paediatrics, modelling and simulation, and clinical pharma-
cology when designing paediatric clinical trials. This ensures
not only the necessary expertise for optimising sampling
schemes in paediatric studies, but also assures the
development and selection of appropriate validated pharma-
codynamic endpoints to study of drug effects in children.
These initiatives together will lead to a lower burden for
each participating child with a higher scientific output.
2.2 Analysis of paediatric pharmacokinetic data
Due to ethical and practical constraints in the volume and fre-
quency of blood sampling, paediatric datasets typically con-
tain a limited number of observations per patient. The
application of the so-called ‘population approach’ has opened
new avenues for drug research in vulnerable patient groups
which are otherwise difficult to study, such as neonates,
infants and children [5]. This population approach involves
the application of Nonlinear Mixed Effects Modelling, in
which all data of all patients are simultaneously analysed, tak-
ing into account that different samples originate from differ-
ent patients, yielding estimations of pharmacokinetic
parameters, their inter-individual variation and intra-
individual variability. An important feature of this approach
is that it allows for the utilisation of sparse and unbalanced
data obtained during routine clinical practice, thereby, keep-
ing the burden on the individual patient to a minimum.
Additionally, relatively dense data or a combination of sparse
and dense data may also be considered.
Population pharmacokinetic modelling and simulation can
be applied throughout the entire development process of
rational and individualised paediatric dosing guidelines:
i) clinical trial simulations combined with D-optimality for
optimisation of limited sampling schemes in clinical trial
designs based on pooled historic data [6-10], ii) development
and internal validation of population pharmacokinetic models
using sparse data, iii) external model validation using
 Knibbe, Krekels & Danhof

Reasonable to assume that

Disease progression is similar
in children and adults?
Reasonable to intervention will be
similar in children and adults?

No Yes to both
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Reasonable to assume that concentration-

response will be similar in children and adults?

No Yes

Is there a pharamacodynamic Conduct pharmacokinetic studies

measurement that can be to achieve levels similar to
used to predict efficacy? those in adults
Conduct safety trials
For personal use only.

No Yes

Conduct pharmacokinetic studies Conduct pharmacokinetic and

Conduct safety and efficacy trials pharamacodynamic studies
to determine concentration-
response for pharmaco-
dynamic measurement
Conduct pharmacokinetic studies
to achieve target concentration
based on concentration-
response
conduct safety trials

Figure 1. Paediatric study decision tree from the FDA to help determine what paediatric trials and studies are required to
derive paediatric dosing guidelines for a drug.
From: Copyright Ó [2007] Massachusetts Medical Society. All rights reserved [54].

independent data and iv) prospective clinical evaluation of
optimised dosing guidelines [3,6].
Using the population approach, difficulties with limited
patient numbers and sparse sampling have now been over-
come. As a result, there are a large number of publications
on population pharmacokinetics of drugs that are subject to
routine therapeutic drug monitoring (e.g., gentamicin [11-13],
amikacin [14]) and on specific population pharmacokinetic
studies (e.g., morphine [15,16], propofol [17], midazolam [18,19],
paracetamol [20,21], tramadol [22,23]). These studies have gener-
ated the pertinent values for pharmacokinetic parameters in
specific patient groups such as neonates or adolescents, and
identified the influence of age-related and non-age-related
covariates such as postnatal age, postmenstrual age, body
weight, organ function and/or concomitant therapy on these
parameters. However, while this is highly important informa-
tion, pharmacokinetic models that describe the entire
paediatric age-range are limited, and so far the predictive
value of these models for extrapolations to other age groups
and/or to other drugs has not been proven in any of
the studies.
The population approach can be considered a top-down
approach studying the net influence of various covariates
on drug pharmacokinetics. Another approach that is

Expert Opin. Drug Metab. Toxicol. (2011) 7(1) 3

 Advances in paediatric pharmacokinetics
gaining in popularity is physiologically-based pharmacoki-
netic modelling, as incorporated in Simcyp and PK-Sim
software [24,25]. This can be considered a bottom-up
approach, in which information on in vitro drug characteris-
tics and information on all underlying biological processes
are combined to simulate pharmacokinetic profiles. With
this methodology, a substantial number of drugs pharmaco-
kinetic profiles have already been successfully predicted in
children [26,27].
2.3Specific aspects of paediatric model development
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and validation
When paediatric datasets are analysed, specific attention is
paid to the covariate analysis. In the covariate analysis, the
influence of age-related physiological changes, which are
quantified by measurable demographics such as age and/
or body weight, is incorporated into the population model.
While this step in the pharmacokinetic modelling process
constitutes the scientific basis for the dosing guidelines in
the paediatric age-range, it is important that these age-
related covariates are studied in conjunction with other
general covariates such as race, genetics or other patient char-
acteristics in a comprehensive covariate analysis. Once the
covariates have been identified, they can be used to individu-
For personal use only.
alise the dose for each child, particularly when covariates are
involved that are readily available when the drug treatment
is initiated (e.g., body weight, age, sex, concomitant therapy),
by dosing on this covariate relation as identified in the
covariate model.
For the covariate modelling process on the influence of age-
related physiological changes on the pharmacokinetics of a
drug, different approaches are currently being applied. Body
weight and age can be considered regular covariates and their
influence on pharmacokinetic parameters can be tested for
significance together with other possible covariates using var-
ious functions (e.g., linear, exponential or allometric) [15,28].
Acceptance of the covariate(s) into the model depends on sta-
tistical significance, full diagnostic and validation procedures,
and biological plausibility; the last is especially important to
consider when correlations in covariates are present [29]. Alter-
natively, in the allometric scaling approach, body weight is
incorporated a priori using an allometric equation with a fixed
empirical exponent of 0.75 for clearance and 1 for distribu-
tion volumes. Subsequently, these equations are augmented
by estimated age-based functions of various natures [30]. This
often leads to a high number of parameters to be estimated
with this approach.
Model validation is essential to corroborate the descriptive
and predictive properties of population models. Unfortu-
nately, this is too often neglected, as results on internal valid-
ity (same dataset, same age-range) and external validity
(different dataset, same age-range) are often not presented [31].
While model validation in paediatric studies is influenced by
the characteristics of paediatric datasets in various ways, it
seems that all these issues can be overcome:
4 Expert Opin. Drug Metab. Toxicol. (2011) 7(1)
1) When sampling in a data set is sparse, estimated values
of the variability in model parameters may shrink to
zero, causing individual post hoc parameter estimates
to move towards the population predictions. This so-
called ‘shrinkage’ causes individual parameter estimates
and diagnostics based on them to be less reliable or
even misleading [32,33]. Diagnostics based on popula-
tion predictions should then be used as they are not
sensitive to shrinkage. Simulation-based diagnostics
such as a visual predictive check (VPC) [34] and normal-
ised prediction distribution error (NPDE) [35] are also
not sensitive to shrinkage.
2) As a result of the many physiological changes that take
place in quick succession, the paediatric population is
very heterogeneous. Stratifying diagnostics based on
body weight or age then becomes important to avoid
for instance bias in the younger patients that corrects
bias in the older patients causing the overall diagnos-
tics of the population to appear to be unbiased.
For simulation-based diagnostics, VIsual Predictive
Extended Residuals (VIPER) has recently been pro-
posed as an alternative for VPC because VIPER, like
NPDE, does not require stratification based on
covariates [36].
3) As paediatric datasets are often limited in the number
of individuals and characterised by sparse sampling,
the external validation of models may be hampered
both by lack of available independent datasets and
by complications resulting from data splitting. This
can be solved by using historic data and by initia-
tives of data-sharing between academic groups
and/or industry.
Because of the importance of the covariate model in
quantifying the influence of maturational changes in a phar-
macokinetic model, for individualisation of the dosing regi-
men, particular attention should be paid to plots that show
individual and population parameter values versus the pri-
mary covariate that was found. These plots of, for example,
clearance versus body weight should demonstrate that the
individual post hoc values for clearance for each individual
child are evenly and non-biassedly spread around the popula-
tion value for clearance over the entire range of body
weight studied.
Taking into account these issues and considerations, inde-
pendent of the choice for a bottom-up approach (physiologi-
cally-based pharmacokinetic modelling) or a top-down
approach (population pharmacokinetic modelling), or the
(covariate) modelling approach (e.g., systematic covariate
analysis or fixed allometric scaling), and despite specific limi-
tations of the paediatric datasets, final paediatric population
(covariate) models can and should be validated and/or
prospectively evaluated using advanced statistical methods
in order to demonstrate a model’s descriptive and
predictive potential.

3. Conclusion
Important advances have been made in descriptive paediatric
pharmacokinetic models on specific drugs and paedia-
tric age-ranges. Furthermore, advanced analysis and diagnos-
tic tools have been identified for the development and
evaluation of paediatric population (covariate) models,
allowing for the development of validated pharmacokinetic
models despite small patient numbers and/or limited and
sparse sampling characteristics of paediatric datasets. Even
though currently none of the scaling approaches has
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proven to be of universal value for extrapolation to
other drugs or other age-ranges, progress is being made in
this area. As a result, empiric and allometric models will
be replaced by models that generate information on the pae-
diatric biological system either using physiologically-based
pharmacokinetic modelling (bottom-up) or population
pharmacokinetic modelling (top-down).
4. Expert opinion
New regulations have led to an increased number of
studies in children in which age-related physiological
changes in pharmacokinetics and pharmacodynamics are
For personal use only.
studied to determine dosing guidelines in children. So far,
a large number of descriptive studies on the pharmacokinet-
ics of many drugs in varying paediatric age-ranges have been
reported. An important question is whether the covariate
relations obtained in these studies are suitable for extrapola-
tion to: i) other age-ranges for the same drug and ii) same
age-ranges but other drugs that share the same metabolic
route (cross validation).
Concerning extrapolation to other age-ranges, it has been
claimed that the allometric scaling approach using a fixed expo-
nent of 0.75 for clearance or 1 for volume of distribution is
based on ‘sound biological principles’ [16] and can, therefore,
provide a basis for extrapolations outside the studied age or
weight-range. However, this has never been proven and both
the biological basis of a single universal fixed exponent in the
body weight-based equations [37-44] and the utility of these
equations in the pharmacokinetics in the human weight-
range [42,44-46] have been highly questioned. Despite these
issues, the fixed value of the exponent of 0.75 for clearance is
often used for the extrapolation from adults to children because
of the lack of other extrapolation approaches. However, it is
recognised that especially in very young infants, allometric scal-
ing with a fixed exponent of 0.75 results in over-predicted
clearance values that need to be corrected by age-based func-
tions [30]. To use this 0.75 value without age-based corrections
in infants under the age of 1 year seems, therefore, hazardous,
especially when dosing recommendations are derived from
these models [47]. Most recently, it was demonstrated that
even with an age-based correction, predictions using fixed allo-
metric covariate models have poor performance in the youngest
age-ranges [48].
Expert Opin. Drug Metab. Toxicol. (2011) 7(1)
Knibbe, Krekels & Danhof
Peeters et al. demonstrated that propofol clearance is not
only over-predicted in neonates, but also under-predicted in
infants around 2 years of age when using the allometric equa-
tion without age-based corrections [49]. More recently, in chil-
dren younger than 3 years of age, a value as high as 1.45 for
the exponent for propofol clearance based on body weight
was found to adequately describe the clearances of these chil-
dren [50]. While it is important to state that this body weight-
dependent model cannot be used for extrapolation to higher
age-ranges, this model was explored for cross validation to
other drugs that are glucuronidated in a population of the
same age-range. It was found that a similar exponent of
1.44 was reported for the glucuronidation clearance of mor-
phine in children younger than 3 years [15]. Furthermore, as
the exponent on body weight in very young populations is
more often found to be higher than 1 and in older paediatric
populations to be lower than 1, a novel model for ages rang-
ing between preterm born neonates and adults has been pro-
posed for propofol, in which the exponent changes with
body weight in a sigmoidal fashion [50]. This offers the advan-
tage of using only one continuous covariate relationship that
reflects the continuous changes in the maturation of clearance
from rapid maturation in neonates (exponent higher than 1)
to slower maturation in older children and adolescents (expo-
nent lower than 1). These results are in line with various stud-
ies of Mahmood which revealed that extrapolation over the
entire paediatric age-range cannot be based on a single fixed
exponent for all drugs [45,46]. It remains now of interest to
test whether this equation can also be used for other drugs
that are glucuronidated.
In contrast, for midazolam, which is mainly metabolised by
CYP3A4, an entirely different covariate relationship has been
reported over the entire paediatric age-range [51,52]. After
6 months of age, no change in absolute clearance values in
millilitre/minute was found. This implies that for this drug
the same maintenance doses should be used in all paediatric
patients older than 6 months. Instead, dose reductions were
found to be required for midazolam in case of critical illness,
as critically ill children in the intensive care showed four times
lower cyp3A4-related clearance values compared to relatively
healthy children [51].
However, if for each drug a model needs to be fully devel-
oped and validated over the entire paediatric age-range large
costs and a significant amount of time will be involved to
develop evidence-based paediatric dosing guidelines. An
important question is, therefore, to what extent developed
covariate models constitute a basis for the development of
dosing guidelines for drugs other than those that have actually
been studied (cross validation).
A specific feature of mechanism-based pharmacokinetic
models is the possibility to make a distinction between drug-
specific and biological system-specific parameters to character-
ise the time course of the drug effects [53]. In this respect, the
maturational changes in functionality of drug metabolising
enzymes, drug transporters, as well as the expression and
5
 Advances in paediatric pharmacokinetics

0.12 CLM3G = 0.00202 × BW 1.44

0.10
drug system
specific specific
Clearance [L/min]

0.08 property property

0.06

CLM6G = 0.00105 × BW 1.44

0.04
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Universite De Sherbrooke on 11/28/12

0.02

0 5 10 15
Bodyweight [kg]

Figure 2. The covariate relationship between body weight and clearance of the morphine metabolites morphine-
3-glucuronide (M3 G, black) and morphine-6-glucuronide (M6 G, grey) in children younger than three years. The dots and
lines represent individual and population clearance values, respectively. The first terms of the equations determine the
magnitude of clearance, which is hypothesised to be a drug-specific parameter that is different for each drug. The second
term of the equations determines the shape of the covariate relationship which is hypothesised to be a characteristic of the
For personal use only.

biological system, which is the same for each drug that is eliminated through the same route. Both morphine metabolites are
eliminated through renal clearance; the magnitude of the clearance is different for the two different metabolites, but the
maturation rate of this process was found to be the same for the two metabolites.
Adapted from [15], with permission from Adis, a Wolters Kluwer business (Ó Adis Data Information BV [2009]. All rights reserved) [15].

function of pharmacological receptors are system-specific
properties. The system-specific properties derived from one
‘model drug’ could theoretically serve as a basis for the predic-
tion of maturational changes in the pharmacokinetics and
pharmacodynamics of other drugs. These concepts are very
similar to those that provide the basis for physiologically-
based pharmacokinetic modelling and both methodologies
should, therefore, be considered to complement one another.
In physiological pharmacokinetic approaches, all maturational
changes in all underlying physiological processes are character-
ised to simulate pharmacokinetic profiles, whereas population
pharmacokinetic approaches only analyse the net results of all
these changes on specific elimination routes. The physiology-
based approach requires much more data than the population
approach; however, the obtained data are potentially more
broadly applicable.
The finding that the glucuronidation capacity in the neona-
tal period increases in a similar fashion for both morphine and
propofol [15,50] supports the idea that maturation of specific
metabolic pathways is a system-specific rather than a drug-
specific property and that information gained from these
‘model drugs’ can be used for the covariate model of other
drugs that share the same metabolic pathway. Figure 2 illus-
trates this concept with an example of the renal excretion of
the two main morphine metabolites, where the maturation
rate of eliminations can be described using the same covariate
model, but where the magnitudes of clearance differ between
the two metabolites.
The ultimate objective of research efforts in paediatric
pharmacology should, therefore, be the development of
mechanistic and validated pharmacokinetic and physiological
models for specific elimination routes that have predictive and
extrapolation potential to other age-ranges and/or other
drugs. Meanwhile, validated pharmacodynamic endpoints
need to be developed for the paediatric population to facilitate
studies on drug effects in this population, which similarly
allow for the description of the influence of maturation on
the system-specific pharmacodynamic parameters. The use
of model-based simulations using this type of system-
specific information may significantly reduce the costs and
time needed to develop these guidelines for individual drugs.
To assure safety of these guidelines, there should be a strong
emphasis on the validation of the used models and
proposed algorithms.
In order to facilitate these paediatric studies, it is important
to establish a multi-centre infrastructure to collect pharmaco-
kinetic, pharmacodynamic and physiological databases in
children. Sharing of data between groups remains crucial in
order to limit additional burden to individual children. This
approach allows not only for the identification of covariate
relationships that describe the influence of maturational
changes on the pharmacokinetics of drugs over the entire

6 Expert Opin. Drug Metab. Toxicol. (2011) 7(1)

 Knibbe, Krekels & Danhof

paediatric age-range, but also for the identification of Declaration of interest

other covariates such as genetics, race or other patient charac-
teristics in a comprehensive covariate analysis for the proper
(external) validation of models and last but not least for cross
validation to substances that are metabolised through the
same route. Ultimately, these efforts result in the design of
algorithms to derive first-time-in-child doses for new drugs
and individualised dosing guidelines for existing drugs
in paediatrics.
The work of CAJ Knibbe is supported by the Innovational
Research Incentives Scheme (Veni Grant, July 2006) of the
Netherlands Organization for Scientific Research (NWO).
The work of EHJ Krekels was performed within the frame-
work of the Dutch Top Institute Pharma project number
D2-104. M Danhof has no conflicts of interest and has
received no payment for the preparation of this manuscript.

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Affiliation
Catherijne AJ Knibbe†1 PharmD PhD,
Elke HJ Krekels2 MSc &
Meindert Danhof3 PharmD PhD
†
Author for correspondence
1
Professor of Individualized Drug Treatment,
University of Leiden,
Leiden/Amsterdam Center for Drug Research,
Division of Pharmacology,
Leiden, The Netherlands and
St. Antonius Hospital,
Department of Clinical Pharmacy,
PO Box 2500,
3430 EM Nieuwegein,
The Netherlands,
Tel: +31306092612;
Fax: +31306093080;
E-mail: c.knibbe@antoniusziekenhuis.nl
2
PhD candidate,
Leiden/Amsterdam Center for Drug Research,
Division of Pharmacology,
Leiden, The Netherlands
3
Professor of Pharmacology,
Leiden/Amsterdam Center for Drug Research,
Division of Pharmacology,
Leiden, The Netherlands