Cap.8 Farmacologia 2011

R E A L A C A D E M I A N A C I O N A L D E M E D I C I N A
c a p í t u l o
8
CLINICAL PHARMACOLOGY: DO WE NEED
TO REFOCUS OUR ACTIVITIES? A PERSONAL
PERSPECTIVE
C. Dollery, L. López Lázaro, M. Pan
LO QUE ENCONTRARÁ EN ESTE CAPÍTULO:
NM MEDICINA
The role of clinical pharmacology?
New challenges
H ow should we refocus CP to improve patient
care by promoting safer and more effective use
of medicines in the face of rapidly expanding
DE knowledge of existing medicines and a substantial
number of new ones with novel actions?
NACIONAL H ow to refocus cp to increase knowledge through
research?
Choice of dose
Attrition
A Efficacy markers
ACADEMIA Pharmacogenomics and CP
Pathways and networks to new drug
combinations
How to refocus to pass on knowledge through
teaching?
R C p teaching, is divided by the iuphar into knowledge
REAL and understanding, skills and attitudes with
emphasis on critical drug evaluation
Conclusion

REAL ACADEMIA NACIONAL DE MEDICINA
DESARROLLO DE LA FARMACOLOGÍA CLÍNICA EN ESPAÑA
Clinical pharmacology, the study of the pharmacological action of drugs in a
clinical setting, merges seamlessly into therapeutics and includes a wide range of
sub-disciplines (pharmacokinetics, drug metabolism, clinical trial design, safety
monitoring, etc.). At its core is the acquisition of a detailed knowledge of the ac-tions
of medicines in man, both desirable and undesirable, and using that knowl-edge
to improve the risk-benefit balance of these medicines when used in treat-ment
of sick patients. In some academic medical centres “translational medicine”
is now used as an alternative designation to clinical pharmacology. However, this
term both conceals the essential two-way exchange of knowledge between basic
pharmacology, clinical pharmacology and clinical medicine and the central role
that medicines play as the main pathway, whereby scientific advances lead to im-provements
in human health.
In its early days clinical pharmacology was able to expand rapidly because of
two factors. The first of these was the obvious need for physician scientists with
specialised knowledge to investigate in man the avalanche of new medicines that
were launched between the early 1950’s and the late 1970’s. The second was their
ability to fill gaps in the clinical specialities in areas like high blood pressure and
asthma, where it was relatively easy to measure pharmacodynamic responses in
man. Since then the expansion of clinical sub-specialties has made it more dif-ficult
for clinical pharmacologists to practice as front line clinicians unless they
acquire an additional qualification in a clinical sub-specialty (cardiovascular, on-cology,
psychiatry, etc.) as well as training in clinical pharmacology. This need
not be too serious a barrier, provided those who specify training requirements in
both clinical pharmacology and the clinical sub-specialties act in a flexible and
responsible manner. It is important to emphasise that core clinical pharmacol-ogy
requires a thorough understanding of the clinical problems, often multiple in
older patients, and of the various medicines being administered to treat them. One
benefit of this holistic, patient orientated, approach to clinical pharmacology is it
often leads to simplification of the patient’s prescriptions with a gain in efficacy
and a very substantial reduction of side-effects.
THE ROLE OF CLINICAL PHARMACOLOGY?
112 R A N M
The definitions made of the role of clinical pharmacology in the WHO Technical
Report “Clinical Pharmacology Scope, Organization and Training (1), the scope
of Clinical Pharmacology (CP) included [1] to improve patient care by promoting
safer and more effective use of drugs, [2] to increase knowledge through research,
[3] to pass on knowledge through teaching; and [4] to provide services e.g., analy-sis,
drug information and advice on the design of experiments. These definitions
still apply, but the constantly changing modern medical world has thrown up
many new challenges for CP. Rapidly expanding knowledge of molecular biol-ogy,
cell biology, genetics and structural pharmacology, and the introduction of
new drugs with novel actions have added greatly to the scientific and medical
interest of CP, but has also brought home to the clinician clinical pharmacologists

CLINICAL PHARMACOLOGY: DO WE NEED TO REFOCUS OUR ACTIVITIES? A PERSONAL PERSPECTIVE
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that they cannot achieve the WHO objectives alone. Within the Pharmaceutical
Industry, the meaning of “clinical pharmacology” has drifted from what is consid-ered
in academia, including all aspects of drug action in humans to acquire a very
specific meaning restricted to clinical pharmacokinetics/ pharmacodynamics, the
design and conduct of the initial clinical studies usually performed in healthy
subjects, and some biomarker related activities. As it will be developed during
the article, Clinical Pharmacology and the Industry may be reinvigorated from a
clinical pharmacology approaching the original meaning.
Hence, the simple answer to the question, “do we need to refocus”, posed in the
title of this article is: yes, constantly.
New challenges
In this article, recent scientific and medical developments which pose a need
for CP to refocus its activities are analysed and possible ways to improve are
proposed.
For activity [1] “to improve patient care by promoting safer and more effec-tive
use of drugs” the need to refocus comes from: a) the ever increasing number
and diversity of drugs; b) the expansion of knowledge about existing drugs; c)
a much more detailed knowledge of the molecular mechanisms underlying the
aetiology and progression of existing and novel diseases; and d) not least, much
greater emphasis on drug safety. There is also a need to expand CP’s therapeutic
horizons. Many clinical pharmacologists have neglected the challenge posed by
protein therapeutic agents, despite the fact that these have been some of the most
effective new drugs of the last decade. The next therapeutic frontier seems likely
to be epigenetics, the area of science that deals with the methylation of DNA,
readers, writers and erasers that utilise acetylation or methylation of histones for
influencing the expression of families of genes (2), micro RNAs -the human ge-nome
has about 1000 of them, with 1048 unique entries found in a query to MIR-BASE
(3,4)- that modulate RNA polymerases, etc. CP neglects those at its peril.
If it chooses to live in a comfortable world of G-protein coupled receptors and the
main cytochrome p-450 drug metabolising enzymes in the course of time it will
gradually lose its relevance to clinical medicine.
For activity [2] “to increase knowledge through research”, the hope that genet-ics
would reveal many new drug targets, and better ways of attacking old ones,
has been fulfilled in areas such as oncology and virology but less so in many other
areas of general internal medicine where the aetiological mechanisms of disease
appear to involve a multiplicity of small factors rather that a single large one such
as the over expression of Her2 in about one fourth of breast cancers (5). Research
on effects of medicines on integrated biological systems at organ and organism
(systems physiology and systems pharmacology) has been neglected in the ex-citement
created by the sequencing of the human genome and it is an area where
CP can play a major role in revival of clinical research. Drug safety has emerged
as one of the most important areas for the expansion of clinical pharmacology

research, and here genetics is beginning to make an important contribution. The
need to refocus on drug safety in the late phase was given great momentum by the
discovery of an increased risk of cardiovascular events during treatment with the
selective COX-2 inhibitor, rofecoxib, and strongly reinforced for the early phase
by the very serious adverse effects in healthy volunteers of the TeGenero super-agonist
antibody TGN1412. These events have had a major influence in shaping
drug development, adding to its cost, and decreasing productivity at a time when
the opportunities opened through the explosion of knowledge about human ge-nome,
biochemistry, physiology and pathophysiology were full of promise.
For activity [3] “to pass on knowledge through teaching”, its implementation
has been impeded by changes in the medical school curriculum in many advanced
countries towards ‘problem orientated teaching’ and away from systems teaching.
This has made it more difficult to teach the principles underlying both basic and
clinical pharmacology, rather than just their application to a few specific clinical
situations. Complaints that newly qualified medical doctors know little about how
to use medicines effectively and safely are having an effect in revitalising the CP
component of the medical schools curriculums, but there is still a long way to go.
The services provisions listed in activity [4] of the WHO list, such as analysis,
information and design of experiments, are essential for without them many of
the objectives outlined in points [1] and [2] will not be achieved. In the pharma-ceutical
industry there is renewed emphasis on ‘experimental medicine’ meaning
small scale, very carefully designed and monitored studies in patients to better
understand the range of actions of novel medicines. In large scale clinical trials
the interest is shifting from simple questions such as, “was there a statistically
significant difference between active treatment and placebo” to more sophisti-cated
efforts to try to understand why some patients responded particularly well
and others scarcely derived any benefit. These activities have to be backed up by
sophisticated studies of drug metabolism and disposition, pharmacokinetics and
investigation of the correlation between pharmacokinetics and pharmacodynam-ics
(PK/PD).
HOW SHOULD WE REFOCUS CP TO IMPROVE
PATIENT CARE BY PROMOTING SAFER AND MORE
EFFECTIVE USE OF MEDICINES IN THE FACE OF RAPIDLY
EXPANDING KNOWLEDGE OF EXISTING MEDICINES
AND A SUBSTANTIAL NUMBER OF NEW ONES WITH
NOVEL ACTIONS?
114 R A N M
The number of approved medicines is high and increasing. The FDA Orange
Book 26th edition (2006) contained products with a total of 1,323 active ingredi-ents
(6). New approvals are a continuous process, even if slowing lately, with 18,
24 and 25 approvals of new drugs in 2007, 2008 and 2009, respectively by the
FDA Center for Drug Evaluation and Research (plus the approvals by the Center
for Biologics Evaluation and Research, about 10 in 2009) (7). The total number

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of approved drugs worldwide is higher, as the list of approved drugs varies among
countries. The knowledge behind each drug is also increasing. FDA Approval
Packages are typically documents of between 50 and 1,500 pages (8) and more
or less unreadable for all but the regulatory experts. The equivalent EMEA docu-ments,
the European Public Assessments Reports (EPAR), the EMEA website
advises being selective when printing as the document may exceed 50 pages for
the EPAR, not including the Scientific Discussion (9). Regulatory agencies and
pharmaceutical companies expend great efforts on approving labelling for medi-cines.
These are shorter than the documents cited above but they are sufficiently
complex for few physicians, and even fewer patients, to read them thoroughly.
Clinical pharmacologists can make a real contribution by distilling the essentials
from these regulatory documents in their teaching role, particularly for new medi-cines
that do not yet have entries in local or national formularies. The magni-tude
of the information explosion can be judged from the number of citations in
Medline, which has increased from 1,098,015 in 1970 to 6,769,918 in 1990 and
17,641,559 in 2009 (10).
As a consequence, learning the appropriate use of information sources is a must
for the clinical pharmacologist, not just for their own use, but to assist in commu-nicating
reliable information to medical practitioners and ultimately to patients.
No single source is sufficient, although regular reading of the top weekly medical
journals such as the New England Journal of Medicine and the Lancet, and the
monthly clinical pharmacology journals, Clinical Pharmacology and Therapeu-tics
and the British Journal of Clinical Pharmacology, is a good start. The Iowa
Drug Information Service keeps track of 200 peer-reviewed English language
medical and pharmaceutical journals (11). This type of service is useful for spe-cific
searches, but Medline currently lists 5,394 journals. Thus additional sources
are needed to be used for at least part of the searches.
Keeping track of this huge amount of knowledge is just a start. The knowledge
has to be evaluated, organized and conveyed to the care providers. Drug evalu-ation
is an increasingly challenging task for which the clinical pharmacologist,
possessing knowledge of medicine, pharmacology and pharmacokinetics is par-ticularly
well suited. One of the gaps that many are now trying to fill is how to
communicate the balance of risk and benefit of a form of treatment in a simple
and intelligible way to front line practitioners and to their patients. It is no easy
task but with the clinical pharmacologists knowledge base it should be possible to
weed out many minor issues and focus on the smaller number that really matter.
If clinical pharmacologists need a slogan it might be, “We are here to optimise the
balance of benefit and risk of your medicines”.
Evidence Based Medicine (EBM) tools provide a good starting point but must be
interpreted intelligently with full regard to the situation of the individual patient.
EBM has been defined as “the conscientious, explicit, and judicious use of current
best evidence in making decisions about the care of individual patients, although
in practice it is often more focussed on groups than individuals. The practice of
EBM for the clinical pharmacologist means integrating an assessment of the clini-cal
situation of the individual with the best available external clinical evidence

from systematic research” (12). There are traps that must be avoided, particularly
converting intelligent use of medicines into “cookbook medicine” as pointed out
by Sackett et al. (12). For many reasons too much of the medical literature can
be misleading, and some is just plain wrong. The clinical pharmacologist must
learn to distinguish good evidence from bad by identifying poorly designed clini-cal
trials, authors who draw sweeping conclusions from small samples, etc. Well
designed, large controlled clinical trials are rightly regarded as the gold standard
of EBM, but the clinical pharmacologists must be aware of important limitations.
The entry criteria usually limit patients to the disease under study without other
intercurrent illnesses; other exclusion criteria may mean that the patients selected
are healthier than the average with that disease, clinical management of patients
in a trial is of a higher standard than is normally available and so on. When a new
medicine is launched a few thousand patients may have been exposed to it but the
number of patient years of exposure may be quite low < 1,000. Once on the mar-ket
the medicine will be given to a wider range of sick people, often with multiple
diseases, less intensive supervision and care delivered by less skilled physicians.
One of the duties of a clinical pharmacologist assessing drug safety is to try and
foresee circumstances of use that may cause serious adverse effects. Professor
Desmond Laurence in his lectures about clinical pharmacology used to say that,
“the largest category of adverse drugs effects were those that were foreseeable but
not foreseen”.
A 3-step conditional model of evidence based decision making has been pro-posed
(13). In the first step, the decision scenario is recognized. In the second, a
simple contextual strategy is applied. In the third, a more complex strategy is en-gaged
if necessary to resolve discrepancies between guidelines and specific cases.
This 3-step strategy may help avoiding the cookbook style and the curtailment of
individual thinking, while the second step allows consistent thinking in common
situations.
When the clinical pharmacologist is considering recommendations for groups
rather than individuals, it is important to recognise that most clinical assessments
are made under time pressure and advice given to front line physicians should
concentrate on the essentials, both those that will optimise the benefit and those
that will help to minimise common mistakes. CP can easily lose its credibility
with physicians seeking advice by over emphasis of scientifically interesting but
clinically low priority detail.
Evidence based medicine forms the basis of the new field of Health Technol-ogy
116 R A N M
Assessment (HTA), which, with a few notable exceptions, has emerged in
the absence of CP contributions (14). Health Technology Assessment is defined
by the National Institute of Health Research of the United Kingdom National
Health Service (NHS) in their webpage (15) as independent research about the
effectiveness of different healthcare treatments and tests for those who use,
manage and provide care in the NHS. It identifies the most important questions
that the NHS needs the answers to by consulting widely with these groups, and
commissions the research it thinks is most important through different funding
routes.

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At a time of constrained resources, HTA is in the forefront of deciding policies
about affordable healthcare and there is an important role for clinical pharmacolo-gists
in helping those who make these difficult decisions at national, local and,
sometimes, individual level.
HOW TO REFOCUS CP TO INCREASE KNOWLEDGE
THROUGH RESEARCH?
Choice of dose
There is an old saying in the pharmaceutical industry that the most common er-ror
in early studies of a new drug is to get the dose wrong. The TeGenero incident
illustrated this in a particularly dramatic way and the reactions it generated in the
health authorities and the public opinion is still today, 4 years after it happened
(March 13, 2006), a major driving force.
TGN1412 is a recombinantly expressed, humanized superagonist monoclonal
antibody targeted to CD28 that stimulates and expands T cells independently of
the ligation of the T-cell receptor. In contrast to almost all other antibodies in clini-cal
use or in clinical trials, TGN1412 directly stimulates the immune response in
vivo (16). This knowledge should have triggered a very cautious attitude to early
studies in man because of the past history of cytokine storms triggered by mol-ecules
that could activate T cells.
In preclinical models, including primates, the stimulation of CD28 with
TGN1412 preferentially activated and expanded type 2 helper T cells and in par-ticular
CD4+CD25+ regulatory T cells, resulting in transient lymphocytosis and
occasional lymphadenopathy, with no detectable major toxic or proinflammatory
effects (16). TGN1412 was also tested against human blood cells but unfortunate-ly
using cells suspensions which showed little reaction. These data were used to
construct a no adverse effect level (NOAEL) in accordance with FDA guidelines
and the starting dose was set as a fraction of the NOAEL. Research conducted
after the event with human white cells adhering to a surface showed that there was
a strong cytokine release and calculations showed that the “low” starting dose of
this superagonist was sufficient to occupy about 90% of the CD28 receptors and
thereby trigger a massive cytokine release (17).
When TGN1412 was administered for the first time to human healthy subjects,
6 healthy volunteers were dosed with the active compound at 10 minute intervals.
This was a very serious error of judgement for any compound that might have seri-ous,
acute, adverse effects. By the time the last one was dosed the first was already
developing symptoms. Over the following hours, all became critically ill with lung
injury, renal failure and disseminated intravascular coagulation and required ICU
admission with intensive cardiopulmonary support and dialysis. Prolonged cardio-vascular
shock and acute respiratory distress syndrome developed in 2 subjects,
who required intensive organ support for 8 and 16 days. All subjects survived. In-vestigations
showed that the underlying reason was a massive release of multiple
type 1 and type 2 cytokines (16).

An investigation ensued including GMP inspections of the production sites and
of the facilities, equipment, quality systems, documentation and records associ-ated
with the storage, preparation and release of TGN1412 and placebo at the
unit, GLP inspections of the preclinical studies and a GCP inspection of the study
conduct. These inspections did not show any problems related to the substance
itself and equipment used that might explain the incident (17).
The incident was further investigated by a pharmaceutical industry working
party (Early Stage Clinical Trial Taskforce, Joint ABPI/BIA Report 4th July,
2006) and an Expert Scientific Group appointed by the UK medicines regulatory
agency. An extensive report was issued (17,18) containing recommendations on
the performance of early clinical trials, particularly with molecules judged to be
high risk. The EMEA Guidelines on Strategies to Identify and Mitigate Risks
for First-in-Human Clinical Trials with Investigational Medicinal Products (19)
largely followed these recommendations.
The report drew attention to the need to assess the nature and intensity of the
target effects, particularly those connected to multiple signalling pathways, or
those capable of triggering biological cascades of cytokine release. Instead of
using the no adverse effect level to calculate the first dose, the industry working
party recommended calculation of the “Minimum Anticipated Biological Effect
Level” (MABEL). Although MABEL was designed to deal with situations of par-ticularly
high risk it has general applications. The consequences for CP applied
to early development are clear. The calculation (and where possible pre-clinical
experimental verification of it), should be the main basis for selecting first doses
in man. NOAEL tells the clinical pharmacologists where not to go, not where to
start. The pharmaceutical industry enquiry (18) that preceded the governmental
one, pointed out that a one line calculation using the number of CD28 receptors on
circulating white cells and the number of molecules of antibody delivered would
have shown that the starting dose used with TGN1412 would cause a maximal
response. This was a particularly easy calculation with TGN1412, as the number
of circulating white cells and the number of CD28 receptors per cell was already
known. Agoram (20) has published several more complex examples of MABEL
calculations. Although MABEL was designed to deal with situations of particular-ly
high risk it has general applications and is widely used in industry as a standard
118 R A N M
method. The consequences for CP applied to early development are clear. The
calculation of MABEL should be the main basis for selecting first doses in man.
NOAEL tells the clinical pharmacologists where not to go because of possible
toxicity; MABEL shows where it is safe to start.
TGN1412 highlights the need for CP training to include understanding of the
cellular and molecular basis of drug action (21) and the tendency of some training
programs to omit these is a serious mistake, at least for clinical pharmacologists,
academic or industrial, involved in drug development. The recently published
conclusions by IUPHAR about Clinical Pharmacology in Research, Teaching and
Health Care includes among the core CP competences the knowledge of the gen-eral
mechanisms of action of drugs at a molecular, cellular, tissue and organ level,
the ways in which these actions produce therapeutic and toxic effects the qualita-

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tive and quantitative concepts related to the receptors as targets of drug action
and the tolerance concept (14). Clinical pharmacology must be both clinical and
pharmacological.
The use of the MABEL approach is also useful in critical review of the toxico-logical
information in preclinical species. Pre-clinical drug safety assessment is
heavily based towards structural changes in tissues visible under the microscope
and does not always pay sufficient attention to the magnitude and consequences
of pharmacological effects that may be hazardous but do not cause obvious tissue
injury. Fortunately safety assessment practice is changing and the use of healthy,
conscious, unrestrained animal for medium term studies of pharmacological ef-fects
is growing. Clinical pharmacologists of the future would do well to gain an
understanding of the clinical pharmacology of unrestrained animals used to assess
medium term product safety and pharmacological actions.
Attrition
The sequencing of the human genome unleashed a wave of enthusiasm that the
molecular causes of disease would soon be known and many new potential drug
targets would be found in human genes. Although this outcome has been partly
achieved, especially for discovery of new targets, the anticipated flood of new
medicines has not been realised. Despite massive increases in research spending,
the flow of new products has steadily decreased. This has occurred despite an in-crease
in the number of new chemical entities being launched into development.
Unfortunately a very high proportion of these have failed.
Reducing attrition has become a major preoccupation of the pharmaceutical in-dustry
(22). A number of explanations for high attrition have been advanced, includ-ing
the entry bar for new drugs is higher because they are competing with an en-hanced
standard of care, the regulatory authorities are more demanding, particularly
about demonstration of safety, and developability issues with new molecules. The
automation of early stages of drug discovery in the 1990s contributed, as the mol-ecules
produced by high throughput screens (HTS), were usually selected because
they had high affinity for their targets. These HTS “hits” often had a high molecular
weight (> 500) and high lipid solubility (cLogP > 5). This often meant they had poor
develop ability and safety characteristics, both pre-clinically and in man (23).
Clinical Pharmacology can play a very important role in reducing attrition rate,
going right back to the choice of novel targets and the choice of the candidate
molecule in drug development. These days this means more than simply produc-ing
a new medicine that is as good as the best existing marketed agent. In devel-oped
countries most medicines are now purchased by government agencies or
health insurers, not by the individual patient. These purchasers increasingly take
the view that a novel medicine can only command a premium price for innovation
if there is a clear, measurable, clinical advantage. A clinical assessment of likely
benefit risk, even at a very early stage of drug development, should be made by a
clinical pharmacologist.

By 2000, the major reasons for drug attrition during development were lack of
efficacy (~30%) and safety (toxicology and clinical safety) accounting also for
~30%. CP must pay close attention to preclinical safety as for common problems
such as liver toxicity that has substantial predictive power. If the preclinical safety
issues are not of sufficient concern to halt progression, it is essential to devise a
monitoring strategy in man that is designed to detect an adverse effect before
serious problems arise. If safety problems occur in clinical studies, the clinical
pharmacologist has an important role in trying to ensure that a very well docu-mented
clinical narrative is obtained as without it, assessment of cause and effect
may be problematic. If there is serious toxicity, a DNA sample should also be ob-tained.
Recent research had demonstrated that a number of medicines that caused
“idiosyncratic” toxicity have a strong association with human leukocyte antigen
(HLA) groups. These include abacavir, flucloxacillin, clavulanate, lumiracoxib
and ximelgatran (24,25). These compounds have no structural motifs in common
and the associated HLA group varies. A hope that has been realised with abacavir
is that the HLA group associated with the adverse reaction is uncommon and the
toxicity can be avoided by excluding patients with that HLA group (26).
An important objective is to try and secure evidence of efficacy and safety very
early in the development of a new medicine. Great effort is being made to dis-cover
new biomarkers that will provide an early signal of efficacy or raise an issue
about safety. The motto is “if the molecule is going to fail, fail it early”.
Efficacy markers
Late phase clinical trials are usually required to have hard end points such as
myocardial infarction and dementia. In early phase trials it is extremely useful
to have markers of drug response that will give an indication of efficacy after
relatively brief periods of administration. Few medicines, if any, are beneficial to
everyone treated and in most cases there is a wide range of response. The desire
to predict patients who will respond particularly well to a medicine is a keystone
of personalised medicine. Some of the most successful examples have been in
oncology, the over expression of Her2 in about one fourth of breast cancers (5),
the Bcr-abl fusion protein in chronic myelogenous leukaemia (CML) (27) and the
V600E mutation in BRAF in about 40% of malignant melanomas (28).
The search for new biomarkers of drug response has concentrated on substances
that are measurable in plasma or serum. Many of these are long established such
as T3, T4 and TSH in thyroid disease, cortisol to assess adrenal cortical function,
CRP for inflammatory activity, etc.
Much effort had been devoted to the study of new metabolic (metabolomics) or
protein (proteomics) changes in disease that can be used as biomarkers to assess
disease response. The central problem of many new proposed biomarkers is the
lengthy process required to validate that changes in their concentration are closely
linked to the disease process and have a reasonable degree of specificity. A very
large numbers of biomarkers have been accepted to track inflammatory processes,
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particularly cytokines such as TNFalpha, IL6 and IL10, NT-proBNP is valuable
as an early marker of cardiac stress, the N and C-telopeptide of type 1 collagen
as a measure of bone turnover, cardiac troponin-I and troponin-T as a marker
of myocardial cell injury due to ischemia or other reasons, etc. Each of these
required thorough and lengthy clinical assessment before being widely accepted
and the same or greater stringency will be needed to be used for the large number
of novel biomarkers now being investigated. Even the use of existing ones for
new purposes needs extensive validation. Small changes in troponin-I well below
the levels indicative of serious myocardial ischemia are being explored in safety
assessment to detect myocardial injury caused by medicines. There is a significant
role for CP in the thorough and even handed investigation of new biomarkers to
assess drug response, particularly safety. New biomarkers often fail to live up to
their early promise from the laboratories of enthusiasts.
Pharmacogenomics and CP
The best examples of genetic influences on drug response are drawn from
polymorphisms of drug metabolising enzymes. The majority of medicines are
eliminated from the body by metabolism by cytochrome p-450s and/or glucuro-nyl
transferases in the liver followed by excretion of the metabolites in urine or
bile. There are some well known polymorphisms of cytochrome p-450s including
CYP2D6, CYP2C9 and CYP2C19. A number of older drugs such as fluoxetine
and paroxetine are metabolised by CY2D6 and individuals with the reduction of
function polymorphism have a higher concentration of the drug in their plasma
(29). Conversely gene duplications of CYP2D6 can have serious consequences
for patients taking codeine as a greater proportion is converted to morphine (30).
Most pharmaceutical companies now design medicines to avoid a CYP2D6 liabil-ity
so it is likely to be a declining problem. The CYP2C9 gene has a large number
of polymorphisms and about one third of a Caucasian population carries at least
one allele of CYP2C9 associated with reduction of function (31). CYP2C9 me-tabolizes
a number drugs including, including phenytoin, losartan, fluvastatin and
warfarin (32). Warfarin is particularly interesting as another polymorphic gene,
VKORC1, encodes the vitamin K epoxide reductase and thereby influences the
response to warfarin. Screening patients for polymorphisms of the VKORC1 and
CYP2C9 genes has improved the accuracy of choosing the starting dose of war-farin
for anticoagulation (33).
However, experience suggests that the clinical use of pharmacogenomics to
guide therapy has proved beneficial with only a small fraction of drugs in general
use (34). In most cases the number of factors governing the plasma concentration
and the PK/PD relationship is too large to make useful predictions.
The expectations from using genetics to select appropriate treatment of chron-ic
diseases have tended to ignore the very large changes in phenotype that take
place as a disease progresses. A smoker aged 40 may have a chronic cough, slight
impairment of lung function and little disability. The same individual aged 60

may have severe disability with poor lung function, a chronic cough with pus
laden sputum and suffer from winter episodes of cor pumonale, CO2 retention
and hypoxia. The patient’s genes are the same but the treatment required is very
different. This is an example, of which there are many, where the clinical pharma-cologist
must consider the phenotype, particularly the duration and severity of the
disease, of the individual as well as the genotype when making recommendations
about the best line of treatment.
Pathways and networks to new drug combinations
Most body control systems interact in complex biological networks and pertur-bations
of these networks contributes to the disease state (35) a feature which con-nects
with an emerging paradigm in pharmacology which needs to be understood
and assimilated by CP, the so-called “network or pathway pharmacology”. This
concept underlies an approach to drug design that encompasses systems biology,
network analysis, connectivity, redundancy and pleiotropy (36). The basis for this
approach is the observation that single gene knockouts in model organisms have
in most cases little or no effect on phenotype (36). This robustness of phenotype
can be understood in terms of multiple feedback loops, redundant pathways and
alternative compensatory signalling. This inherent robustness of interaction net-works
has profound implications for drug discovery; instead of searching for the
“disease-causing” genes, network biology suggests that the strategy should be
to identify the perturbations in the disease-causing network (36). Gene expres-sion
studies have a role to play in uncovering these but much of the progress will
come from exploration of physiological pathways in higher animals. In the net-work
pharmacology paradigm, promiscuity would help efficacy. As partial practi-cal
validations of this prediction, a retrospective review of marketed CNS drugs
showed that promiscuity in molecular actions is the rule rather than the exception
(37). This concept has important implications for designing drug combinations
that may be more effective and safer. Instead of a high degree of inhibition of
one component a less intense effect at different nodes in a complex pathway may
yield a more favourable outcome (38). The standard treatment of many common
diseases such as tuberculosis, cancer and hypertension usually involves the use of
more than one drug. These have evolved and been tested over long period using
combinations of marketed drugs. A very important part of the future of thera-peutics
122 R A N M
lies in the choice of logical combinations of different agents, based on
genetics, systems physiology and pathway analysis and it is an area where clinical
pharmacologists need to play a major role.
As an example of the activities leading to the development of these logical
combinations of drugs, in March 2010, the Critical Path to TB Drug Regimens
(CPTR) initiative (39) was launched by the Bill & Melinda Gates Foundation,
the TB Alliance, and the Critical Path Institute. This group of partners joined
with pharmaceutical and biotechnology companies, civil society organizations,
and many others to takle the challenges facing the search for novel, simpler, and

123
R A N M
faster-acting tuberculosis regimens, including the uptake of a regulatory and clini-cal
model that can speed combination drug testing. FDA supports this initiative
as well as other regulators around the world. CPTR provides a platform that will
help pave the way forward for combination drug testing. This can be an example
for other areas were combination therapy is standard like oncology, malaria and
hepatitis C. New Combination 001, NC001, (40) is the TB Alliance´s first clinical
trial to test a novel tuberculosis regimen. This phase II early bactericidal activity
trial evaluates the combination of PA-824, moxifloxacin, TMC-207, and pyrazin-amide
for its ability to shorten treatment for both drug-sensitive and multidrug-resistant
tuberculosis to less than six months.
Last, but not least within the contribution of CP to drug development, the tradi-tional
fields of pharmacokinetics, pharmacodynamics and its relationship is also
quickly moving and requires a retooling. A new term has been coined, pharma-cometrics,
which is defined as the science of quantifying disease, drug, and trial
characteristics with the goal of influencing drug development and regulatory and
therapeutic decisions (41). This science evolved by including first pharmacoki-netics,
later linked to pharmacodynamics. Later (1979), mixed effects modelling,
sparse sampling schedules, labeling statements pertaining intrinsic and extrinsic
factors supported by pharmacometric analyses, and quantitative disease and clini-cal
trial models added to this discipline (41).
The possibilities created by pharmacometrics, including already by 2000 the
use of clinical trial simulation to guide actual drug development and optimize the
dosage of docetaxel (42) oblige CP to remain in the forefront of this discipline.
The mathematical complexities and other factors make necessary the collabora-tion
with other professionals but the presence of CP as a bridging discipline is
necessary. To fulfill its tasks, a working knowledge of pharmaconetrics, without
shying away at its mathematical complexity, should be part of the CP training.
PK/PD modelling is now a standard art of the evaluation of new medicine (43),
and there are extensive software programs to facilitate it (ModelMaker, WinNon-lin/
Phoenix, NONMEM, Clinical Trial Simulator, a programming environment
such as R/Splus, Perl, or SAS, Monolix). A word of caution is necessary however.
Model building must be pursued in close conjunction with iterative experimenta-tion
and be based on physiological not abstract parameters. In many cases PK/PD
relationships are quite weak because of the underlying variability of the disease
aetiology and severity. A clinical pharmacologist working with a modeller should
build a close personal understanding and ask many questions about the underlying
assumptions on which the model is based. The outcome will be a better under-standing
of the relevance of the model by the clinical pharmacologist and a more
useful model for the modeller.
How to refocus to pass on knowledge through teaching?
As recently re-stressed by IUPHAR (14), “Teaching is a vital part of the work of
a clinical pharmacologist; although all doctors and many health care professionals

need regular education concerning drugs, perhaps the most important area current-ly
is the training of new prescribers which is primarily new physicians as pharma-cists
and nurses do comparatively little prescribing when looked at in a worldwide
sense. The ability of new young physicians to prescribe safely and effectively has
been criticized in recent years and new systems are being developed so that much
more attention is paid to these skills in the training of medical students.”
CP TEACHING, IS DIVIDED BY THE IUPHAR INTO
KNOWLEDGE AND UNDERSTANDING, SKILLS AND
ATTITUDES WITH EMPHASIS ON CRITICAL DRUG
EVALUATION (14)
Clinical Pharmacology embraces a very wide range of activities from conduct-ing
first administration to man of new medicines, through large scale clinical tri-als,
personal delivery of patient care to helping make decisions about use of scarce
financial resources to achieve the best possible outcome of the therapeutic use of
medicines in the community. If one thing is clear a clinical pharmacologist can-not
be an expert in all these areas. However, to be effective in any of them it is
essential to have a good understanding of the pharmacological action in man, be
able to make a critical assessment of risk and benefit for the individual patient in
therapeutic use and to keep up to date with new developments in relevant clinical
medicine and basic science.
As noted earlier the amount of information is huge and ever increasing, and
the internet provides rapidly growing sources of opinion and “disinformation” to
patients and prescribers. Managing the information explosion to improve medical
care will be a major preoccupation of CP for the next decades. Already studies
are in progress using automated internet reminders to achieve better adherence
to prescribed medication and telephone administered questionnaires to check on
well being and side-effects. It is easy to foresee that the physician of the near
future will have a personalised, password protected, part of his practice web site
for each of his patients with the ability of the patient and physician to exchange
email messages or videos about problems and progress. Already remote outposts
are making use of these methods to obtain specialist medical advice at a distance.
Many of these patients’ queries will be about adverse effects of medicines or
lack of efficacy. The practice clinical pharmacologist, in addition to direct care
of his own patients, will act as a consultant to his colleagues who receive queries
that they cannot handle and will also seek by education and review to raise the
standards of all. As in every other branch of medicine the clinical pharmacologist
will have to demonstrate continued competence periodically by participation in
continuing professional development and an annual appraisal.
By service on local formulary committees or on regional or national health
boards, clinical pharmacologists are bound to become involved in decisions about
the cost-benefit of medicines for the community, as well as deploying their profes-sional
124 R A N M
training in risk-benefit for individuals. This is not an easy role, for it in-

125
R A N M
volves weighing the needs of the individual patient for a medicine that may be very
expensive, against the needs of the wider population for a range of other medical
interventions that compete for resources. In this situation CP should neither adopt
the role of a policeman enforcer of prescribers, or an advocate for use of a particu-lar
product. Instead, put the facts about a particular medicine before colleagues and
decision makers and ensure that it is as accurate and dispassionate as possible.
Many clinical pharmacologists will work in the pharmaceutical industry play-ing
a critical role in the development of new medicines for the all-too-common
clinical situations where the best existing treatment is far from ideal. Here too it is
important that that they exercise their expertise in a dispassionate and judgemental
manner. It serves no-one’s interests to become an advocate for a compound that of-fers
little therapeutic advantage and harbours the possibility of as yet unidentified
risks. The need for highly qualified clinical pharmacologists in the pharmaceutical
industry is great, for they play a critical role in the transition of new molecules
from laboratory to bedside and a continuing role in the choice of dose and safety
monitoring in late phase trials. The scientific and clinical process of developing
a new medicine is extremely stimulating and intellectually rewarding. It should
never be forgotten that the community depend upon industry to deliver the new
medicines that are so much needed, particularly for an aging population. In turn
the pharmaceutical industry is heavily dependent upon the academic scientific
and medical community to create a better understanding of the mechanisms caus-ing
and maintaining human disease and to collaborate in the investigation of new
medicines. Academic and industrial clinical pharmacologists must build a good
working relationship based on mutual trust and sharing expertise, and in their
common commitment to their discipline and the patients they serve. By working
together they can achieve much more than by negotiation through intermediaries,
particularly with small scale intensive studies of novel medicines.
Recent initiatives based on public-private partnerships such as the Innovative
Medicines Initiative (IMI) jointly launched by the European Commission and the
European Federation of Pharmaceutical Industries and Associations offer oppor-tunities
to foster these collaborative networks (http://www.imi.europa.eu). There
is already evidence that realisations can be achieved in this context (44).
CONCLUSION
This article began with a question, “Do we need to refocus clinical pharmacol-ogy”.
It ends with an emphatic’ “yes”. Not because existing CP is tired and boring
but because it faces an extremely exciting and varied future full of novelty and
fresh scientific insights. CP has a major role to play in: a) the discovery and devel-opment
of new medicines; b) ensuring that they are used in a manner to optimise
benefit and minimise risk for patients; c) to do so as economically as possible; and
d) to communicate clear and accurate information to practitioners and patients
about the management of illness with medicines. All this represents a great chal-lenge
to CP, but can you think of a more interesting career?

Disclaimer: LLL has participated in the writing of the article as an independent
individual without connection with his employment in Covance. The statements,
opinion and views contained in the article have to be considered as those from
LLL as an individual co-author and not as sustained, endorsed or in any other
way linked to Covance.
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