Dc\/ICt>f A BTI/~I C Clin Pharmocoklnet 2008:47 (Ó): 373-381

KcVtcW M K T I C L C 0312-5963/08/0006-0373/S48,00/0
O 2008 Adis Data Intormatlan BV. All rights reserved.

Pharmacokinetic and Pharmacodynamic Data to

be Derived from Early-Phase Drug Development
Designing Informative Human Pharmacology Studies
Adam Cohen
Centre for Human Drug Research, Leiden, the Netherlands

Contents
Abstract 373
1. The Translational Approach 374
2. Objectives of Human Pharmacology Studies 375
2.1 Does the Compound Reach the Site of Action? 375
2.2 When the Compound Has Reached the Site of Action, is the intended Pharmacoiogicai Effect Accompiished? 376
2.3 When Adequate Drug Concentrations Are Reached at the Site of Action, is the Pathophysiology of the Disease Modified
Such that Effects on the Disease Can Be Measured? 376
2.4 is There an Acceptable Window between the Concentration-Response Curve for Clinical Effects and Adverse Effects? 377
2.5 in Which Circumscribed Popuiation Do the Observed Effects Occur? 377
3. Design 377
3.1 Crossover or Paraiiei Designs 377
4. Measurements 378
4.1 Pharmocokinetics 378
4.2 Pharmacodynamics 379
4.3 Fiexibility in the Protocol 379
4.4 Risk Analysis 379
4.5 Modeliing and Simuiation 379
5. Conclusions 380

AbStrOCt Drug development is, in essence, the answering of scientific questions related to the effects of the intended
new medicine. This process starts with preclinical research and proceeds with clinical testing. Especially for
innovative drugs, this proceeds along a numher of cycles in which the questions are answered by learning from
informative studies and subsequent confirmation in more pragmatic studies. Many first-in-human studies and
other human pharmacology studies are not designed to be informative but use standard designs and answer
generic questions about tolerability and safety. Despite several recent and eloquent pleas for more integrated and
quantitative drug development, signs of a strong uptake of this are lacking. In this article, an orderly method for
the determination of objective human pharmacology studies is given. The objectives of the study and the
expected pharmacology and pharmacokinetics of the compound determine the optimal design; and several
general design models and guidelines are given for the design of informative human pharmacology studies.

The first administration of a new medicinal substance to a
human being is an important event for the scientists who discov-
ered the drug, for the investigators who administer it and, not least,
for the subjects who receive it.
The uncertainty connected with drug development and the
attempts to resolve it by experiments are hampered by the fact that
animal experiments are not always predictive of the human situa-
tion. Especially for substances with a mechanism that is untested
in humans, this extrapolation is uncertain, and tbe first data from
human studies resolve many of these uncertainties. Uncertainty
extends beyond the moment when the drug is given for the first
time into the period of dose escalation, during multiple dosing, and
374 Cohen

when the drug is first given to patients. Administration of new
compounds to humans in early phases of drug development is
generally considered safe,''' but serious accidents have happened,
resulting in long-lasting disabilityt^l and even death.'^-'*' When such
a study is designed, the researcher is caught between the general
uncertainty induced by the absence of human data and the require-
ments of subject safety on the one hand, and the objective to get as
much data as possible on the other.
Designing a study with a relatively new drug is therefore not a
trivial matter that can be addressed using standard designs. The
objectives of these studies cannot be solely described as evaluation
of tolerability, as is often stated. The tolerability of the drug in
humans is obviously an outcome but certainly not the primary or
sole objective. The guideline on clinical trials issued by the US
FDA'^i and the European Medicines Agency (EMEA) states this
explicitly (table I) by defining the multiple objectives of human
pharmacology trials as being definition of pharmacodynamics and
pharmacokinetics, estimation of therapeutic activity (when appro-
priate), and study of metabolism, interactions and tolerability. The
FDA guideline also indicates that the attribution of phases (I-IV)
to drug development is an oversimplification and that the terms
used in table I should be used instead. Restating this is of impor-
tance as, for unknown reasons, most human pharmacology is
described as either phase I or tolerability trials. Drug development
is basically a continuous process of reduction of uncertainty
through experimental data in humans. It is recognized that the
amount of information obtained from any stage in the research and
development cycle has to be maximized. The 'learn and confirm'
paradigm that was introduced by Sheiner'^' is a good model for
this. The FDA's Critical Path Initiative'^' is an initiative to stimu-
late more informative and innovative development. There is a
clear case being made for using new evaluation tools to obtain as
much information as possible in early translational studies. This
overview is to provide initial guidance for the design of early
human pharmacology studies, with the general aim being to ex-
tract the maximum amount of data possible, which we call data-
intensive human pharmacology. If these data are obtained early
and reliably, the human pharmacology study can be an important
factor in the quantitative approach to drug development.'^'^'
1. The Translational Approach
Luckily, the first-in-human trial is not an isolated event. A host
of preclinical data normally precede it and can be used to support
the design and the methodology of the trial.
However, preclinical development is not always fully suited to
the development of the drug in humans. In modem translational
drug development, the aim of the preclinical work is not to
produce a set of data that complies with the guidelines, but rather
to produce an integrated body of knowledge. In general, this
requires the use of methodology that somehow provides a link to
the next stage of development. Specific solutions go beyond the
scope of this article.
There is one translational marker that is still underused: the
concentration of the active compound and its metabolites in
animal experiments that deal with the mechanism of action of the

Table I, A reclassification of ciinical triais according to the objective rather than the phases of developmental
Type of study Objective of study Study examples
Human pharmacoiogy Assess tolerance Dose-tolerance studies
Define/describe pharmacokinetics/pharmacodynamics Single- and multiple-dose pharmacokinetic and/or
Explore drug metabolism and drug interactions pharmacodynamic studies
Estimate activity Drug-interaction studies
Therapeutic exploratory Explore use for targeted indication Earliest trials of relatively short duration in weli
Estimate dosage for subsequent studies defined narrow patient popuiations, using surrogate
Provide basis for confirmatory study design, endpoints, or pharmacologicai endpoints or clinical measures
methodoiogies Dose-response exploration studies
Therapeutic confirmatory Demonstrate/confirm efficacy Adequate and well controlled studies to estabiish
Establish safety profile efficacy
Provide an adequate basis for assessing the benefit/risk Randomized, parallel-group, dose-response studies
reiationship to support licensing Clinical safety studies
Establish dose-response relationship Studies of mortality/morbidity outcomes
Large simple trials
Comparative studies
Therapeutic use Refine understanding of benefit/risk relationship in Comparative effectiveness studies
general or speciai populations and/or environments Studies of mortality/morbidity outcomes
identify less common adverse reactions Studies of additionai endpoints
Refine dosing recommendation Large simple triais
Pharmacoeconomic studies

© 2008 Adis Data Information BV. All rights reseived. Clin Pharmacokinet 2008:47 (6)
PK/PD Data from Early-Phase Drug Development
drug. The majority of pharmacological model studies are done on
the basis of a mg/kg dosage, and the resulting concentrations in
blood or near the receptor site are rarely measured. Clearly, this is
a missed opportunity to relate the results to findings in other
species and to plan the dosage in humans.
In a review of the preclinical data for ten first-in-humans
studies in the past 2 years in our clinical research unit (table II), it
was found that the plasma concentration was rarely measured
directly in the pharmacological models. Additionally, there was no
assurance that the primary pharmacological model occurred in the
toxicology species. The dosage in humans was generally deter-
mined on the basis of the 'no observed adverse event level' of the
dose in animals (NOAEL) and not on the expected pharmacologi-
cally active dosage (PAD), recently renamed as the 'minimally
anticipated biological effect level (MABEL).^^"" In many cases,
the only parameter observed in the first-in-human studies was the
occurrence of side effects rather than quantitative biomarkers
(other than the plasma concentration) [table II]. This sample
cannot be considered as fully representative, but it reflects the
practice following the Critical Path Initiative paper by the FDA.'^l
Despite the eloquent pleas that have been made for model-
based drug development,^^' it is clear that in many cases the basic
data to do this simply are still lacking. The trial with TGN 1412,
which led to severe adverse effects in six healthy volunteers who
had to be hospitalized and suffered long-term sequelae, was a case
in point. Despite the fact that both the pharmacology of this
compound and the expected concentrations were well defined, the
starting dose of the compound was chosen on the basis of the
tolerability only in an animal species. If a pharmacological ap-
proach had been chosen, it would have revealed that the first dose
would have produced over 90% receptor binding,!^'"' in addition to
other factors that were overlooked.'^' In addition, the study had as
its main objectives the tolerability and safety of the compound,
rather than the immunopharmacology. While it is obvious that this
study reached its objective of demonstrating intolerability and lack
of safety, it is equally obvious that this is not the way to do this and
that this study may well have attempted to evaluate an inappropri-
ate dosage. Many drugs on the market require subsequent dosage
reductions.f"' Although better human pharmacology may not pre-
vent all of these, the traditional dose-finding methodology in large
clinical trials cannot always differentiate between dosages well
enough to allow a rational choice of dosage for later-phase trials.
Knowledge of receptor binding and other pharmacological effects
in relation to plasma concentrations is helpful in making this
choice. There may therefore be an urgent need to revise the current
practice of human pharmacology trials which, besides pharmaco-
kinetics, does not normally require quantitative assessment of drug
action in the early phases.
Therefore, despite the existence of many conceptual articles
and guidelines regarding the scientific and quantitative approach
© 2008 Adis Data Information BV. Aii rights reserved.
375
Table II. Review of ten investigators' brochures for drugs to be adminis-
tered to humans for the first time in 2006 and 2007^
Marker %
Use of concentrations in animal modei 30
Use of concentrations in toxicology models 70
Pharmacological effect in toxicoiogy assured 0
PAD or model-based dosage selection 30
NOAEL-based dosage selection 90
20
Concentration-based first time in humans
Tolerability only endpoint 60
Biomarker-based endpoint 50
a This demonstrates that use of concentrations in animal
pharmacology is still uncommon. Additionally, the dosage for human
studies is selected rarely on the basis of the PAD and more often on
the basis of the tolerability in the toxicology species (NOAEL).
NOAEL = no observed adverse event level; PAD = pharmacologically
active dose.
to early human pharmacology studies, it appears that the penetra-
tion of these principles in the field is low. In this article, some
general practical guidelines are given for the design of studies to
produce meaningful results in addition to the traditional tolerabili-
ty and safety objectives.
2. Objectives of Human Pharmacology Studies
Writing the objectives of a study is not easy, and no standard
that can be applied to any compound exists unless one chooses to
use the 'safety and tolerability' objective. An orderly approach
towards choosing and prioritizing objectives has been given by de
Visser"^' in a concept called question-based drug development
(QBD). This can be used to make an inventory of all unanswered
questions as guidance for the development of an informative
human pharmacology study. This approach was designed to be
valid for the full range of development studies and, clearly, some
aspects are of less relevance to the early studies. The concept is,
however, given in full. Figure 1 gives the basis for the logical
progression of questions to be asked in human research.
There are five basic headings for the objectives.
2.1 Does the Compound Reach the Site of Action?
The main objectives are to determine if the drug reaches the site
of action and how long it resides there. Clearly, this is connected
with traditional pharmacokinetics in the blood, but it may also
involve more sophisticated measures in tissue, microdialysis or
concentration measurements in other material such as sputum or
urine. This analysis will therefore force the designer of a protocol
to think through all of the options and choose relevant ones for the
particular drug.
Clin Pharmacoi<lnet 2008; 47 (6)
376 Cohen

Population
shown not to be), but the primary requirement of accomplishing
Site the intended phannacological effect for long enough can be
Administration reached.
l
Absorption
This can sometimes be accomplished directly or ex VÍVO''^! and
is the basis for pharmacokinetic-pharmacodynamic modelling. A
Distribution challenge experiment in which an agonist is administered and the
effect is measured after administration of the antagonist also gives
Metaboiism Eüminatiorí"
Pharmacology indirect information about the kinetics of the concentration at the
Action site site of action,""'^' as we have demonstrated in several therapeutic
fields.
Pharmacoiogicai ' ' Pharmacoiogicai
effect i effect i i... n
To do such an analysis for a new compound requires good
Clinical knowledge of the pharmacology and the available measurement
Aetioiogy of Aetioiogy of
adverse effect
techniques. Sometimes new techniques have to be developed to
disease
get adequate measurements, as with the analysis of concentrations.
Pathophysiology Pathophysiology In some therapeutic fields, a host of unvalidated parameters exist

i 1 (especially the CNS field), and careful selection based on the

Disease Window Adverse effect
modification (coilateral)
Fig. 1, Guidance for question-based determination of objectives for trials.
The five main headings for the questions are outlined in relation to the
factors that determine the action of a pharmacologically active
Measurement of drug concentrations at the site of action - for
instance, in the hrain - may require special techniques such as
positron emission tomography (PET) imaging. The biomarkers for
these measurements are obviously the concentrations of the com-
pound and metabolites, but this does require a thorough evaluation
of the expected sensitivity of the assay and its validity in the
chosen materials. Also, the analysis indicates immediately if fur-
ther method development (or development of tracer drugs) is
required.
literature and pilot experiments is essential.''*"^" One can perform
exactly the same analysis for the measurement of adverse effects,
and of course the pharmacology of the primary effect overlaps
with the pharmacology of the adverse effects where overdosing is
concerned. Collateral pharmacology'^^' causing adverse effects
can also be measured (for instance, sedation produced by certain
Clearly, all of these measurements are dependent on the pres-
ence of adequate biomarkers that are suitable for obtaining an
answer to the questions posed. If new biomarkers or measurement
techniques have to be developed, and if this is only discovered late
in the process, it is unlikely that they will be available in time.
Therefore, early identification of such problems, preferably at
least 2 years before entry into human studies, is essential if at all
possible.

2.2 When the Compound Has Reached the Site
af Action, Is the Intended Pharmacological
Effect Accomplished?
Measuring the pharmacology of the compound is not necessari-
ly the same as measuring the clinical effect but does provide
reassurance that the intended pharmacology does occur in humans.
Measurement of pharmacodynamics is often described in general
terms, but it is useful to realise that one is studying pharmacology
only. For instance, measuring the inhibitory effect of the aldose
reductase inhibitor tolrestat in red blood cells provides evidence
that a certain plasma concentration is necessary to inhibit the
enzyme continuously''^^ by using a pharmacokinetic-pharmacody-
namic model. It does not give any reassurance that the drug is
active for the prevention of diabetic neuropathy (which it was
2.3 When Adequate Drug Concentrations Are Reached
at the Site of Action, Is the Pathophysioiogy of the
Disease Modified Such that Effects on the Disease Can
Be Measured?
The clinical effects of a drug have been defmed as positive
effects on 'feelings, function or survival','^^'^^1 and the evaluation
thereof generally requires simpler biomarkers and larger trials; and
this falls outside the scope of this article. However, the data
obtained from disease models can be the beginning of proof of the
clinical concept of a new medicine by getting the correct dosage.
An example is asthma, where the pharmacology can be studied
using an agonist-antagonist model in humans and the effect on the
infiammatory disease can be studied using an allergen challenge

© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (6)
PK/PD Data from Early-Phase Drug Development 377

2.4 Is There an Acceptable Window between the Table IV. A two-group crossover design with ascending doses (A to E) and
Concentration-Response Curve for Ciinical Effects piacebo control (P)^
and Adverse Effects? Subject Study occasion
1 2 3 4 5 6 7
This analysis requires integration of the previous findings and
1 A B P C
generally is done close to the registration of a drug; and is again
beyond the scope of this article. However, the whole early devel- 2 A B P C
opment, done in a rational manner, eventually supports this ana- 3 A P B C
lysis and greatly facilitates the final approval by regulatory bodies. 4 P A B C
This has been recognized by the FDA in a recent viewpoint.'^'' 5 C D E P
6 P C D E
2.5 in Which Circumscribed Population Do the Observed 7 C P D E
Effects Occur? 8 D
C E P
This analysis is relevant in early human pharmacology, and a The two groups of four subjects receive overlapping doses. This
concerns phenotypical characteristics of the study population, design can be expanded and modified with a high degree of
such as racef^^"^°l or age, as well as the genotype, either of drug- flexibility. The problems are carryover effects and dropouts, but
these are diminished compared with the crossover design in table III.
metabolizing enzymes or of receptor types, affecting the 'site' or
the 'pharmacology' questions. Increasingly, this will be part of the
description of the study population. 3.1 Crossover or Parailel Designs

3. Design The advantage of a crossover design is that the number of

subjects can generally be lower. This is of particular value when
The design of human pharmacology studies is dependent on the measurements are made that have high intersubject variability and
nature of the compound under study, but some guidelines can be low intrasubject variability. In addition, subjects always start with
given with regard to the design. Many designs are possible, and a low dose so that any form of hypersusceptibility to the effects of
although a standard approach is often used for first-in-human the treatment is more likely to be detected early. Pharmacodynam-
studies, this is not in any way mandatory or part of regulatory ic measurements in the CNS often have these properties. The
guidance. The general design requirements are well described in disadvantages are also obvious. Carryover of drug effects is a
the relevant guidance documents.'^'^'' The choice of the design problem, and so the washout period must be long enough to
largely depends on the questions that one wants to answer in the remove these. When drugs with potentially very long half-lives are
trial. Several common designs for human pharmacology studies studied, such a design becomes unpracticable. Some of these
are shown in tables III, IV, V and VI. These design types can be effects can be dealt with by randomization of the order of treat-
modified at will by increasing the number of subjects or the ment administration. In first-in-human studies, this is not possible
number of dosages, or by putting in positive (or negative) control as the dose is escalated. The studies have a built-in bias induced by
treatments in addition to or replacing placebo. time and sequence, and this may be considerable in longer cross-
over trials. Another problem is that when subjects drop out, a
Table III. A crossover design in eight subjects with three ascending doses replacement has to go through the whole sequence again, which
(A, B, C) and placebo control (P)^ may delay the end of the trial. This can be remedied by the
Subject Study occasion inclusion of additional subjects, although this in itself produces
1 2 3 4 ethical problems connected to the exposure of an unnecessary
1 A B P C number of subjects.
2 A B P C The 4-5 subject-per-panel design (table IV) with ascending
3 A P B C doses is probably the best choice for the crossover ascending dose
4 P A B C
trial. In this design, small panels of subjects are used. This has the
advantage that at the early stages of the study, when low (and
5 A B C P
subsequently irrelevant) doses are often used, the subject numbers
6 P A B C
are low. The overlap produces higher subject numbers at several
7 A P B C
stages during the dose progression. In addition, dosing panels may
8 A B C P be repeated (when there is a requirement for more data) or the
a The advantages of this design are a low number of subjects and overlap of doses may be increased (when a more careful progres-
safety. The problems are carryover effects and dropouts. sion of escalation is warranted). This provides considerable fiexi-

© 2008 Adis Data Information BV. Aii rights reserved. Ciin Pharmacoi<inet 2008: 47 (6)
378 Cohen

Table V. A two-group design with overlapping progression of ascending The full parallel design (table VI) is most frequently used and is
doses (A to D) and placebo control (P)^ considered standard by many researchers. However, the safety of
Subject Study occasion the subjects is least assured, as some subjects receive the higher
1 2 3 4 dose without any experience at the lower doses. As any form of
1 A P higher susceptibility to adverse effects is unlikely to be detected
2 A P
anyway in these trials (using 5-10 subjects per dose group), the
risk can be considerable. The design type where alternating groups
3 A C
are used (where subjects within the group receive lower doses
4 A C
first) may be a compromise. This design makes use of the largest
5 P c number of individual subjects, which is an advantage because it
6 P c exposes a larger population, and it is undoubtedly the most effi-
7 P D cient for time.
8 B P The researcher attempting to choose a design can only do so
9 B D with a clear vision of the objectives to be reached. There is little
10 B D doubt that if a limited and generic objective is chosen, such as
11 B P 'tolerability and safety', the design will be generic. Unfortunately,
12 P D the result will be equally non-informative. Considerable creativity
a The advantage of this design is that a longer washout can be used is possible in early human studies, and this is of special importance
without losing time, and at least some of the advantages of the for drugs with a novel mechanism of action.
crossover with regard to statistical power are still present. Safety is
reduced as subjects progress through the ascending doses with
4. Measurements
iarger steps.

bility and safety, and so this is the ideal design for first-in-human
studies with pharmacodynamic measurements.
Many of the problems can be managed by carefully managing
the entry and exclusion criteria and the trial methodology. For
instance, in the case of a rapid-acting sedative benzodiazepine
drug, the first-in-human trial with a crossover design provided full
pharmacokinetic-pharmacodynamic data regarding the drug and a
comparison with a positive control (midazolam) all in one study
taking <6 weeks.^^^'^^l
Multiple administration of single doses is not possible since it
then becomes a defacto multiple-dose experiment, which may be
unacceptable. Safety problems can also occur where there is a risk
of inducing sensitizing antibodies in the case of biologicals, and
there are other reasons, such as a very long duration of action, why
this design is not always considered to be safe.
4.1 Pharmacokinetics
There is a wealth of general guidance on how to perform
pharmacokinetic studies.^^''•^^1 The pharmacokinetic methodology
must be part of the biomarker analysis for the question group about
concentrations at the site of action. Both the sample handling and
frequency and the analytical methodology should be suited to the
data expected from the trial. In first-in-human studies, unexpected
differences between humans and animals may be seen, and it is
advisable to study the pharmacokinetics after each dose level even
though this requires overtime in the assay lab. These data allow
immediate adjustment of the sampling scheme if the half-life is
different from animal extrapolation, or of the dose if plasma
concentrations are too low or too high.
The importance of obtaining an adequate frequency of samples
to obtain a good description of absorption and elimination
pharmacokinetics is self evident. Intermediate analysis allows the

Table VL Ihe full parailel design with ascending doses (A toD) and placebo control (P)ä
Study Subject
occasion 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
A A P P
B B B P

D D
a Washout is unnecessary, so the study can progress quickly. Statistical power is lower and safety is less, as some subjects receive the higher
doses without any experience at lower doses.

© 2008 Adis Data Information BV. All rights reserved. Clin Piiarnnacokinet 2008; 47 (6)
PK/PD Data from Early-Phase Drug Development
adjustment of sampling times (keeping the total number of sam-
ples the same).
4.2 Pharmacodynamics
Based on a good analysis of the resolvable questions in the trial,
the pharmacodynamic measurements and measurement schedule
can be determined. The type of measurement varies widely and
can be as simple as the haemoglobin (in the case of a study with an
erythropoietin preparation)'^*' or a very complicated CNS chal-
lenge model using PET scanning.'^'^ Both incidentally resolve the
question about the drug reaching the site of action and executing
its intended pharmacology. There is no reason to assume that busy
schedules in early human pharmacology studies would preclude
pharmacodynamic measurement. Careful planning of the protocol
is a prerequisite, however, in addition to having the study per-
formed by adequately trained staff and in a dedicated environment.
4.3 Flexibility in the Protocol
Building flexibility into study protocols is essential if lengthy
waiting periods for further ethical or regulatory clearance are to be
avoided. There are a number of general measures that can be taken
that allow flexibility without jeopardizing the safety of the sub-
jects or ethics.
The European Clinical Trial Directive gives suggestions about
the nature of so-called substantial amendments that require further
ethical/regulatory clearance. However, this list is only intended as
guidance, and the law in the EU now clearly states that the study
initiator or sponsor determines which amendments are substantial.
The law therefore provides an opportunity to follow a proactive
strategy. For example, it is possible to stipulate that dose changes
are allowed and considered non-substantial when they are within
certain boundaries (for instance, specifying that the plasma con-
centration does not exceed a certain value). It is even possible not
to indicate any dose levels other than the starting dose and to give
clear decision rules for escalation while keeping the actual doses
entirely free.
The same goes for measurement schedules. For example, when
it is prespecified that a maximum number of samples (and a
maximum blood volume) is taken within a certain time period, the
timing of the samples can be changed by a non-substantial amend-
ment to the protocol. Use of flexible data management and work-
flow systems (e.g. the Promasys® Clinical Trial Workflow and
Data Management System'^^1) is essential to be able to keep the
data structure intact and interpretable. The practical approach to
this risk-based implementation of the EU directive by different
authorities in the member states of the EU is varied, but the above
strategy is entirely within the scope and the letter of the law.
© 2008 Adis Data Infamnation BV. All rights reserved.
379
4.4 Risk Analysis
The risks involved in an early human pharmacology trial are
multifold. Perhaps the biggest risk, and one that is often incurred,
is that the trial does not reach its objectives. Even if there is no
medical risk to the subjects, they have still undergone procedures
that may have been burdensome for no good reason. For this
reason, thorough analysis of objectives and the feasibility of the
methodology are increasingly demanded by ethics committees and
regulators alike. Assuming scientiñcally sound design and assur-
ance of data integrity, there is still the risk of harm done by the
compound itself. Although there have been recent attempts to rank
new compounds as high- or low-risk,!^^^ this is not easy to accom-
plish. New medicines that are untested in humans always carry a
risk of unexpected serious adverse effects, and relaxation of the
conditions for the so-called low-risk compounds is not advisable,
as misclassification may occur. Therefore, the practical implica-
tions of such an artificial dichotomy could paradoxically be a
reduction in the safety of such experiments. This does not mean
that it is not important to explicitly state the expected risks. We'^l
and others""! have proposed an approach to the qualitative evalua-
tion and communication of risk, using the TGN 1412 incident in
London as an example.
When such a risk analysis is present, other aspects of the trial
conduct can also be outlined. For instance, the amount of medical
and nursing backup and monitoring has to be designed. In the
TGN 1412 incident, six subjects were treated at the same time,
which led to serious problems when their adverse effects had to be
managed in an intensive care unit. These arrangements are again
dependent on existing knowledge about the mechanism of action.
Even if TGN 1412 had had its intended effects, one could have
expected long-term immunosuppression from animal experiments.
Medical problems associated with this would have occurred much
later, and staggering the drug administration by a couple of hours
would most likely not have made any difference.
4.5 Modelling and Simuiation
The science underlying modelling of the relationship between
concentrations, the concentration at the receptor and the response
is mature and can be relatively easily applied. There certainly is an
increase in the use of modelling and simulation for the design of
trials, but less so in human pharmacology. Only a small minority
of the trials in our recent database are based on translational
models, including data from animal pharmacology; absorption,
distribution, metabolism and excretion studies; and clinical stud-
ies. These exercises are done preceding registration,!*"'"! but gen-
erally retrospectively, and good models that are adapted during
development, initially using the data from animal experiments
with subsequent reflnement using the clinical data as they appear,
are still uncommonly used during the human pharmacology or
Clin Pharmacokinet 2008; 47 (ó)
380
therapeutic exploratory phases of drug development, when they
are probably needed most. Additionally, tbe data-intensive trials
that are needed to evaluate biomarkers and develop the models are
still not
5. Conclusions
The planning and conduct of a first-in-human study and other
early human pharmacology studies is not a trivial matter. The
transition between animal and human studies requires evaluation
and integration of a large body of data. This has to be translated
into a good plan. The current investigator's brochures and proto-
cols for first-in-human trials or human pharmacology trials do not
yet reflect the translational approach that is widely advocated by
scientists and regulators alike. This may require a revision of the
common models of collaboration between clinicians, clinical
scientists and drug companies. Additionally, training of transla-
tionally oriented clinical pharmacologists is overdue. We may
have spent too much energy on the process quality of drug devel-
opment, and it is time for a rethink as to where the priorities lie.
Acknowledgements
No sources of funding were used to assist in the preparation of this review.
The author has no conflicts of interest that are directly relevant to the content
of this review.
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Correspondence: Professor Adam Cohen, Centre for Human Drug Research,
Zerrükedreef 10, Leiden, 2333CL, the Netherlands.
E-mail; ac@chdr.nl
Clin Pharmacokinet 2008; 47 (6)