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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 9, 2009
Contents
The Role of Radiopharmaceuticals in Drug Discovery and Development
Executive Editor: Kalevi Kairemo
Editorial: Pp. 926-927
Microdosing, Imaging Biomarkers and SPECT: A Multi-Sided Tripod
to Accelerate Drug Development Pp. 928-934
E.K.J. Pauwels, K. Bergstrom, G. Mariani and
K. Kairemo
[Abstract] [Purchase
Article] [PMID: 19275656 PubMed - indexed for MEDLINE]
Cardiovascular Drug Development Using Radiopharmaceuticals Pp. 935-942
H. Ukkonen, K. Yoshinaga, J.N. DaSilva, R.S.B.
Beanlands and J. Knuuti
[Abstract] [Purchase
Article] [PMID: 19275657 PubMed - indexed for MEDLINE]
Role of Radiopharmaceuticals in Development of Inhaled
Drugs Pp. 943-949
A.P. Jekunen
[Abstract] [Purchase
Article] [PMID: 19275658 PubMed - indexed for MEDLINE]
Cancer Drug Development with the Help of Radiopharmaceuticals:
Academic Experience Pp. 950-956
S.M. Larson
[Abstract] [Purchase
Article] [PMID: 19275659 PubMed - indexed for MEDLINE]
Radiopharmaceuticals for Oncology Drug Development:
A Pharmaceutical Industry Perspective Pp. 957-965
P.S. Murphy and M. Bergström
[Abstract] [Purchase
Article] [PMID: 19275660 PubMed - indexed for MEDLINE]
Defining Pharmacokinetics for Individual Patient Dosimetry
in Routine Radiopeptide and Radioimmunotherapy of Cancer:
Australian Experience Pp. 966-982
J.H. Turner
[Abstract] [Purchase
Article] [PMID: 19275661 PubMed - indexed for MEDLINE]
Cancer Drug Development Using Glucose Metabolism Radiopharmaceuticals Pp. 983-987
Y.Y. Sun and Y. Chen
[Abstract] [Purchase
Article] [PMID: 19275662 PubMed - indexed for MEDLINE]
Development of a PBPK Model for Monoclonal Antibodies
and Simulation of Human and Mice PBPK of a Radiolabelled Monoclonal
Antibody Pp. 988-1007
T. Heiskanen, T. Heiskanen and K. Kairemo
[Abstract] [Purchase
Article] [PMID: 19275663 PubMed - indexed for MEDLINE]
General Articles
Vanilloid Receptor Antagonists: Emerging Class of Novel Anti
Inflammatory Agents for Pain Management Pp. 1008-1026
M. Pal, S. Angaru, A. Kodimuthali and N.
Dhingra
[Abstract] [Purchase
Article] [PMID: 19275664 PubMed - indexed for MEDLINE]
Atheroprotective Properties of Pigment Epithelium-Derived
Factor (PEDF) in Cardiometabolic Disorders Pp. 1027-1033
S-i. Yamagishi, T. Matsui and K. Nakamura
[Abstract] [Purchase
Article] [PMID: 19275665 PubMed - indexed for MEDLINE]
Abstracts
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Editorial: The Role of Radiopharmaceuticals in Drug
Discovery and Development
Radionuclide imaging together with other non-invasive
imaging techniques have found a prominent place in the whole
drug discovery and development process. The application of
imaging has the potential to alter the direction of the development
process. The fundamental questions to address are when in
the development timeline do you use these imaging techniques
and what is the current utilization of these imaging technologies?
Imaging in psychopharmacology and CNS disorders, plays a critical
role in drug development, because often nonclinical models
do not exist (Pauwels et al.) [1]. Structures to
be imaged are often small, location has to be known very precisely
to estimate function disturbances and macrodosimetry is therefore
more accurate. This issue focuses more on the targets outside
the brain, main focus is therefore in cancer drug and cardiovascular
drug development. Dosimetric and pharmacokinetic aspects are
more complex and therefore discussed thoroughly.
In this issue, cardiovascular drug development has been reviewed
by academic network with members from Europe, North America
and Japan (Ukkonen et al.) [2]. In this field there
is an emerging need to understand the effects of drugs. Radiolabelled
compounds offer possibility to study noninvasively cardiac
perfusion, oxygen consumption, oxidative and substrate metabolism,
myocardial efficiency of work, neural actions and receptors.
Radiopharmaceuticals provide invaluable tool to study different
routes of administration. Most cardiovascular drugs are oral
and cancer drugs systemic intravenous. Inhalation provides
benefits over other routes of administration, e.g. avoidance
of firstpass-metabolism, and convenience for patients in administrations
without repeated injections. Drug development of inhaled substances
is complicated and usually development times are longer than
ordinary drug development. The dosage in inhaled drugs causes
many uncertainties as reviewed by Jekunen [3].
Interest in functional imaging techniques has been motivated
especially by FDA exploratory IND guidelines. Pharmaceutical
industry has made substantial investments in imaging centers
throughout the world to assist in the drug development process.
Especially in the area of oncology research by applying radionuclide
imaging techniques to determine the optimal protocol in early
clinical trials. It seems evident that non-invasive imaging
and especially radionuclide techniques will see increasing
use in the drug discovery and development process.
In this issue cancer drug development has been reviewed from
several points of view. New tracers providing molecular insight
into therapeutic intervention are likely grow, and are able
to define processes such as angiogenesis and apoptosis, as
reviewed by Murphy and Bergström [5] from a pharmaceutical
industry point of view. The use of radiolabeled compounds
will support early development decision-making and de-risking
expensive, late-stage programs. Labeled drugs themselves also
offer the ability to study localised pharmacokinetics in
vivo and study issues such as therapeutic combinations
(Murphy & Bergström). Academic experience in anti-cancer
drug development from Memorial Sloan-Kettering Cancer Center
has been reviewed by S.M. Larson [4]. Critical issues are
the pharmacokinetics and pharmacology of novel drugs, including
bioavailability and local tumor concentration and the identification
of the biologic target at the cellular level. Importantly,
clinical cancer therapy is combinatorial therapy, combinatory
effects may be the included to nanocarriers and radioisotope
combinations to improve biodistribution [4]. Radionuclide
image quantification allows to study pharmacokinetics and
pharmacodynamics in a more detailed manner at organ level
if serial imaging has been applied (Turner et al.)
[6]. The evaluation of whole body contents using system biology
approaches may be investigated as presented by Heiskanen et
al. [8].
More than 90 % of clinical PET studies are based on 2-fluorodeoxyglucose,
[18F]-FDG-PET, which has
a critical role in evaluating early metabolic response to
treatment. There is no possibility to construct a similar
SPECT tracer, but similar targets have been used for SPECT
tracer and possible therapy development. Cancer drug development
using glucose metabolism radiopharmaceuticals has been reviewed
by Sun & Chen [7] in this issue. More than 20 monoclonal
antibodies have got their FDA approval for clinical cancer
therapy. In their development radiolabeled constructs have
always been used; however, these have not been extensively
used in the clinics, even though excellent results both in
the diagnostics and therapy occur as the wide Australian experience
demonstrates [6]. These antibody products may be used in combinations
in radionuclide therapy.
New possibilities have been developed to facilitate the drug
development process, such as exploratory IND and microdosing.
The concept of microdosing was originally linked to accelerator
mass spectrometry (AMS), but criteria can be fulfilled with
positron emission tomography (PET) and single photon emission
computed tomography (SPECT) imaging studies. In this issue
especially the possibilities of SPECT and microdosing are
discussed (Pauwels et al.) [1], because PET and AMS
have been reviewed elsewhere earlier.
Novel ‘imaging’ targets may have uncertain relationship
to specific disease states. Acceptable target is of little
value if its action cannot be modulated by therapeutics. Imaging
is a perfect method to assess these target biology questions.
Functional imaging endpoints can be used to evaluate target
effects in normal and diseased models, in different species,
and in the initial clinical studies. The longitudinal results
from functional imaging can be extremely valuable in the evaluation
of data from early clinical trials. The translational potential
of functional imaging techniques is most evident. The uncertainty
in potential drug candidates for example the efficacy and
toxicity can be quickly addressed to determine the course
of action. A preclinical imaging study may produce quantitative
results which can answer these types of translational questions
[1,5]. Imaging may be applied to demonstrate proof of mechanism,
proof of concept and proof of principle.
References
[1] Pauwels EKJ, Bergstrom K, Mariani G, Kairemo K. Microdosing,
Imaging Biomarkers and SPECT: A Multi-Sided Tripod to Accelerate
Drug Development. Curr Pharm Des 2009; 15(9): 928-934.
[2] Ukkonen H, Yoshinaga K, DaSilva JN, Beanlands RSB, Knuuti
J. Cardiovascular Drug Development Using Radiopharmaceuticals.
Curr Pharm Des 2009; 15(9): 935-942.
[3] Jekunen AP. Role of Radiopharmaceuticals in Development
of Inhaled Drugs. Curr Pharm Des 2009; 15(9): 943-949.
[4] Larson SM. Cancer Drug Development with the Help of Radiopharmaceuticals:
Academic Experience. Curr Pharm Des 2009; 15(9): 950-956.
[5] Murphy PS, Bergström M. Radiopharmaceuticals for
Oncology Drug Development: A Pharmaceutical Industry Perspective.
Curr Pharm Des 2009; 15(9): 957-965.
[6] Turner JH. Defining Pharmacokinetics for Individual Patient
Dosimetry in Routine Radiopeptide and Radioimmuno-
therapy of Cancer: Australian Experience. Curr Pharm Des 2009;
15(9): 966-982.
[7] Sun YY, Chen Y. Cancer Drug Development Using Glucose
Metabolism Radiopharmaceuticals. Curr Pharm Des 2009; 15(9):
983-987.
[8] Heiskanen T, Heiskanen T, Kairemo K. Development of a
PBPK Model for Monoclonal Antibodies and Simulation of Human
and Mice PBPK of a Radiolabelled Monoclonal Antibody. Curr
Pharm Des 2009; 15(9): 988-1007.
Kalevi Kairemo, MD, PhD, MSc(Eng)
Consultant in Nuclear Medicine,
Clinical Biochemistry and Clinical Pharmacology
Department of Oncology
Helsinki University Central Hospital
Finland
Helsinki, December 2008
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[Purchase
Article] [PMID: 19275656 PubMed - indexed for MEDLINE]
Microdosing, Imaging Biomarkers and SPECT:
A Multi-Sided Tripod to Accelerate Drug Development
E.K.J. Pauwels, K. Bergstrom, G. Mariani and
K. Kairemo
The advances of nuclear medicine imaging instrumentation
and radiopharmaceutical sciences allow their involvement in
the developmental processes of therapeutic drugs. New chemical
entities, meant as potential drugs, need to comply with the
proof- of- principle. Tomographic imaging methods as PET,
SPECT and CT have been used for small animal and human studies
at an early stage of drug development. Using a drug candidate
in a radiolabeled form in obtaining quantitative imaging data
provides opportunity for a complete morphological and functional
overview of targeting properties and overall pharmacokinetics.
This can be helpful in go/ no- go decision making. Microdosing,
using e.g.1% of the proposed dose of the radiolabeled potential
drug plays an important part in this early development and
notably reduces the risk of serious adverse effects in human
volunteers or patients.
This paper primarily focuses on the way in which microdosing
and SPECT imaging may contribute to the development of drugs.
Furthermore, this paper illustrates how these techniques may
help to eliminate weak drug candidates at early stage, making
time and funds available for potential lead compounds. Eventually
this approach facilitates and accelerates new drug approval.
The present paper highlights how these techniques make drug
development easier in the field of oncology and neurology.
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[Purchase
Article] [PMID: 19275657 PubMed - indexed for MEDLINE]
Cardiovascular Drug Development Using Radiopharmaceuticals
H. Ukkonen, K. Yoshinaga, J.N. DaSilva, R.S.B.
Beanlands and J. Knuuti
Radiopharmaceuticals can provide unique information for
drug development also in cardiovascular applications. Radiopharmaceuticals
offer possibility to study noninvasively cardiac perfusion,
oxygen consumption, oxidative and substrate metabolism, myocardial
efficiency of work, neural actions and receptors, vascular
inflammation, and molecular processes which all are relevant
to understand the effects of drugs. Using these surrogate
end points, hypotheses can be tested in vivo in phase
I and II clinical studies before starting large-scale clinical
phase III or IV trials. In addition, these approaches may
allow improved selection of drug therapy for a given patient.
Modern techniques such as gene therapy technology provide
numerous new potential mechanisms of action and targets for
drug development. Device therapies and cell therapies are
also under rapid development. Molecular imaging has great
potential in evaluating these new therapies and selecting
the patient populations and monitoring of the effect of therapy.
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[Purchase
Article] [PMID: 19275658 PubMed - indexed for MEDLINE]
Role of Radiopharmaceuticals in Development of Inhaled Drugs
A.P. Jekunen
Inhaled drugs have been recognized for their great potential
for improved drug delivery, but so far only a fraction of
their potential is benefiting clinical practice. Many new
promising drug candidates are in development pipelines and
some of them are approaching processes of regulatory agencies.
Overall, investigation in inhalation drug development is intense.
Inhalation administration route provides benefits over other
routes of administration, e.g. avoidance of firstpass-metabolism,
and convenience for patients in administrations without repeated
injections. However, drug development of inhaled substances
is complicated and usually development times are longer than
ordinary drug development. Additional investigational needs
in development of inhaled drugs are dealing with formulation,
devices and variability of respiratory function between human
subjects. Radiopharmaceuticals provide invaluable tool to
explore these issues non-invasively. First, radiopharmaceuticals
can be used in vitro for proof of concept studies.
Second, they are used to resolve depository issues, as well
as to give timeframe for clearance of substances in target
organs. Third, radiopharmaceuticals’ new potential use
is focused on extending non-invasive imaging technique towards
true pharmacokinetic modelling via calculations of
target organ follow-up and exposure. Exposure estimates of
a particular drug candidate make safety evaluation feasible
early in the drug development. Safety issues can be resolved
by investigating exposures of target organs, and depository
and absorption issues in airways.
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[Purchase
Article] [PMID: 19275659 PubMed - indexed for MEDLINE]
Cancer Drug Development with the Help of Radiopharmaceuticals:
Academic Experience
S.M. Larson
In the last decade radiotracers have been gradually growing
in importance as aids for the development of new drugs. This
development has been most pronounced for Psychiatric and Neurologic
drugs [1, 2], but has more recently been adapted to the development
of drugs against cancer. In this mini-review, we describe
how advances in molecular imaging of cancer are likely to
lead to advances in development and improved application of
anti-cancer drugs [3]. We will focus on 4 aspects of use of
radiotracers: 1) for treatment response assessment; 2) for
the study of kinetics and pharmacology of novel drugs, including
bioavailability and local tumor concentration; 3) the identification
of the biologic target at the cellular level; 4) the combination
of nanocarriers and radioisotopes to improve biodistribution.
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[Purchase
Article] [PMID: 19275660 PubMed - indexed for MEDLINE]
Radiopharmaceuticals for Oncology Drug Development: A Pharmaceutical
Industry Perspective
P.S. Murphy and M. Bergström
Oncology remains an increasingly important focus of therapeutic
development yet there remain many scientific and operational
bottlenecks to deliver optimum treatments efficiently. Radiopharmaceuticals
constitute a group of methodologies able to support the many
stages of drug development. Methods such as [18F]-FDG-PET
continue to have a role, evaluating early metabolic response
to treatment and supporting more conventional assessments
of disease response. Improvements over such tracers (for example,
use of [18F]-FLT) in certain
settings can also widen the impact radiotracers have on clinical
development. New categories of tracers able to provide molecular
insight into therapeutic intervention are likely grow and
aim to remove the ambiguity of how effective a new drug is.
It is likely that newer tracers able to define processes such
as angiogenesis and apoptosis will supplement other methods
in supporting early development decisionmaking and de-risking
expensive, late-stage programs. Labeled drugs themselves also
offer the ability to study localised pharmacokinetics in
vivo and study issues such as therapeutic combinations.
Owing to the significant cost, resource and time investment
in developing novel tracers, new opportunities need to be
closely matched with emerging drug development needs.
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[Purchase
Article] [PMID: 19275661 PubMed - indexed for MEDLINE]
Defining Pharmacokinetics for Individual Patient Dosimetry
in Routine Radiopeptide and Radioimmunotherapy of Cancer:
Australian Experience
J.H. Turner
Determination of individual pharmacokinetics in patients
undergoing radiopharmaceutical therapy is essential to define
critical normal organ dosimetry. Review of a 20 year single
institution experience demonstrates practical methodology
for routinely characterising pharmacokinetics in each patient
and calculating safe, effective therapeutic activities predicated
upon prescribed radiation absorbed doses to the critical organs.
In particular the results achieved in over 100 unselected
consecutive clinic patients treated with 131I-rituximab
radioimmunotherapy for relapsed/refractory nonHodgkins lymphoma
have matched the ORR of 75% and CR 50% achieved in formal
phase II clinical trial. The low level of myelotoxicity was
attributed to prospective dosimetry in each patient and prescribed
dose of 0.75 Gy to whole body. Radiopeptide therapy of progressive
neuroendocrine tumours with 177Lu-octreotate,
illustrates application of practical dosimetry using retrospective
quantitative imaging to define individual pharmacokinetics.
Further challenges of multimodality combination therapy using
radionuclide cocktails, chemotherapy and antivascular therapy,
which will perturb pharmacokinetics, will require creative
dosimetric methodology for continued safe, effective clinical
practice of therapeutic nuclear oncology.
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[Purchase
Article] [PMID: 19275662 PubMed - indexed for MEDLINE]
Cancer Drug Development Using Glucose Metabolism Radiopharmaceuticals
Y.Y. Sun and Y. Chen
Imaging of glucose metabolism has resulted in significant
improvements in staging and follow-up in oncology. 18F-FDG
PET has become a routine clinical test for most solid tumours.
Several radionuclide-labeled derivatives of deoxyglucose that
have shown that glucose metabolic imaging may be a useful
tool for improving tumour staging, restaging, and monitoring
of tumour response to therapy.
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Article] [PMID: 19275663 PubMed - indexed for MEDLINE]
Development of a PBPK Model for Monoclonal Antibodies and
Simulation of Human and Mice PBPK of a Radiolabelled Monoclonal
Antibody
T. Heiskanen, T. Heiskanen and K. Kairemo
Physiology based pharmacokinetic (PBPK) modeling and
simulation is a useful method for prediction of biodistribution
of both macromolecules and small molecules. It can enhance
our understanding of the underlying mechanisms of biodistribution
and hence may help in rational design of macromolecules used
as diagnostic and therapeutic agents.
In this review we discuss PBPK modeling and simulation of
a radiolabelled Monoclonal Antibody (111In-DOTA-hAFP31
IgG) (“MAB”) in mice without tumor and in a human
with tumor. This study is part of Xemet Co.’s effort
to develop a more accurate and reliable PBPK model and simulation
platform, which is applicable both for small molecules and
macromolecules.
The simulated results were fitted to experimental time series
data by varying parameters which were not fixed a priori.
It was demonstrated that the PBPK model describes the main
features of the pharmacokinetics of the studied systems. It
was also shown that simulation can be used for evaluating
the parameters of the system and scaling up the pharmacokinetics
of MAB from mice to man.
We identified several areas of improvement and further development
needed to improve the accuracy of PBPK simulation for MAB
and other macromolecules.
It was concluded that the transvascular permeabilities are
the most important parameters and more research is needed
to enable prediction of permeabilities from molecular characteristics
of macromolecules. It would also be necessary to understand
better and describe with a more detailed model the microstructure
of the tumor and to measure or predict the antigen concentration
in tumor. Non-specific, non-saturable binding in other organs/tissues
should be understood better and the kinetic constants of the
binding should be measured experimentally.
Although the metabolism and clearance were neglected in this
study they need to be included in more detailed studies. Also
the intracellular trafficking of macromolecules, which was
not included in this study, shall be included in the more
accurate models.
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Vanilloid Receptor Antagonists: Emerging
Class of Novel Anti Inflammatory Agents for Pain Management
M. Pal, S. Angaru, A. Kodimuthali and N. Dhingra
Neuropathic pain affects 26 million patients worldwide resulting
in a worldwide healthcare cost over $ 3 billion per year.
Despite the availability of an impressive arsenal of powerful
drugs for the effective management of pain, there remains
a great medical need for new medicines to treat pain. While
little is known about the proteins that detect noxious stimuli
(especially those of a physical nature), vanilloid receptor,
an excitatory ion channel expressed by nociceptors, has been
identified as molecular target for the development of recent
therapies to treat pain. Initially, the focus was on the de-velopment
of TRPV1 agonists e.g. capsaicin and resiniferatoxin (RTX)
as analgesic agents through the desensitization/denervation
approach. While various formulations of capsaicin are either
marketed or are currently under development, this approach
is often hindered by the pain and discomfort experienced on
initial treatment. Thus, TRPV1 antagonists are being evaluated
as promising drug candidates to inhibit the transmission of
nociceptive signals from the periphery to the CNS and to block
other pathological states associated with this receptor. Since
the discovery of capsazepine as the first TRPV1 antagonist,
multiple classes of antagonists has been reported that can
be broadly classified as urea/amide-based and non-urea/non-amide-based
agents. However, depending on their chemical structures all
these agents can be grouped as benzenesulfonamides, cinnamides,
ureas, thio-ureas, amides, benzimidazoles, and piperazine
carboxamides, N-aryl-cinnamides etc. The present
review will focus on all these antagonists as an emerging
class of novel, analgesic, anti-inflammatory agents that have
been reported in the literature over the last several years
and the status of the developmental candidates in various
stages of clinical trials.
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[Purchase
Article] [PMID: 19275665 PubMed - indexed for MEDLINE]
Atheroprotective Properties of Pigment Epithelium-Derived
Factor (PEDF) in Cardiometabolic Disorders
S-i. Yamagishi, T. Matsui and K. Nakamura
Although remarkable therapeutic advances in the treatment
of cardiometabolic disorders have been made with current therapeutic
options, cardiovascular disease (CVD) is still a leading cause
of mortality and morbidity in the Western world. Therefore,
to develop a novel therapeutic strategy is needed for the
prevention of cardiovascular disease (CVD) in high-risk patients
for atherosclerosis. Recently, we, along with others, have
shown that pigment epithelium-derived factor (PEDF), a glycoprotein
with potent neuronal differentiating activity, exerts anti-oxidative
and anti-inflammatory properties in vascular wall cells, leukocytes
and platelets. In addition, PEDF not only suppresses neointimal
hyperplasia after balloon angioplasty, but also blocks occlusive
thrombus formation in a rat arterial thrombosis model. These
observations suggest that substitution of PEDF may be a novel
therapeutic strategy for atherosclerosis. This article summarizes
the pathophysiological role of PEDF in atherosclerosis and
its potential therapeutic implication in this devastating
disorder. We also discuss here the kinetics and regulation
of PEDF in cardiometabolic disorders in humans.
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