| Current
Clinical Pharmacology
ISSN: 1574-8847
Current Clinical
Pharmacology
Volume 2, Number 2, May 2007
Contents
Dynamic Contrast-Enhanced MRI in Oncology
Drug Development Pp. 111-122
Hai-Ling Margaret Cheng
[Abstract]
Novel Procedures for Validating Surrogate Endpoints
in Clinical Trials Pp. 123-128
Ton J. Cleophas, Aeilko H. Zwinderman and Amel H. Chaib
[Abstract]
Clinical Trials: How to Assess Confounding and Why
So Pp. 129-133
Ton J. Cleophas and Aeilko H. Zwinderman
[Abstract]
Targeting Ion Channels for New Strategies in Cancer
Diagnosis and Therapy Pp. 135-144
Matteo Conti
[Abstract]
Ethanol Metabolism and Effects: Nitric Oxide and its
Interaction Pp. 145-153
Xin-Sheng Deng and Richard A. Deitrich
[Abstract]
Clinical Efficacy and Effectiveness of Ursodeoxycholic
Acid in Cholestatic Liver Diseases Pp. 155-177
Davide Festi, Marco Montagnani, Francesco Azzaroli, Francesca
Lodato, Giuseppe Mazzella, Aldo Roda, Anna Rita Di Biase,
Enrico Roda, Patrizia Simoni and Antonio Colecchia
[Abstract]
Open Questions on Bioequivalence: An Updated Reappraisal
Pp. 179-189
Antonio Marzo
[Abstract]
Abstracts
[Back to top]
Dynamic Contrast-Enhanced MRI in Oncology Drug Development
Hai-Ling Margaret Cheng
Angiogenesis, long recognized as a key factor in tumor growth
and metastasis, has been the target of new anticancer treatment
paradigms. Development of antiangiogenesis drugs is challenging,
mainly due to the difficulty of determining the correct dosage
and the time required to observe a clinical effect. In the
past decade, imaging has shown potential to answer these questions
and accelerate the drug development process by providing functional,
morphological, and even molecular characterization. In this
review, we describe existing challenges to modern drug development
and the potential of imaging biomarkers to monitor drug bioactivity
and establish early response of drug efficacy. Dynamic contrast-enhanced
magnetic resonance imaging (DCE-MRI), particularly attractive
for its non-invasiveness and high spatial resolution, has
been useful for measuring properties of tumor microvasculature.
The general methodology of DCE-MRI is described, in addition
to measurable hemodynamic parameters compared to other imaging
modalities. Experience with DCE-MRI in antiangiogenesis cancer
therapy and results from correlative studies are examined.
Current challenges for DCE-MRI, especially in relation to
the required sensitivity and reproducibility, are highlighted.
We conclude with an out-look on the future of DCE-MRI, including
its role in the emerging field of imaging molecular markers
of angiogenesis for target-specific therapy.
[Back to top]
Novel Procedures for Validating Surrogate Endpoints
in Clinical Trials
Ton J. Cleophas, Aeilko H. Zwinderman and Amel H. Chaib
Background: The International Conference of Harmonisation
(ICH) Guideline E9 Statistics Principles for Clinical Trials
recommends that surrogate endpoints in clinical trials be
validated using either (1) the sensitivityspecificity approach
or (2) regression analysis. The problem with (1) is that an
overall level of validity is hard to achieve, and with (2)
is that a significant correlation between the surrogate and
true endpoint is not enough to indicate that the surrogate
is a valid predictor.
Objective: To provide for a nonmathematical readership,
procedures that avoid the above two problems.
Results and Conclusions: 1. Instead of the sensitivity-specificity
approach, we used an overall validity level, expressed as
the percentage of patients with a true surrogate test, either
positive or negative. We calculated confidence intervals of
this estimate, and assessed whether they were entirely within
the prespecified interval of validity. If so, the surrogate
marker was validated for use in subsequent trials. 2. For
validating continuous surrogate variables, regression analysis
was used, accounting for both the correlation between the
surrogate and true endpoints, and the associations
between these two variables and the treatment modalities to
be tested. If the proportion of variability in the surrogate
endpoint explained the true endpoint by 70% or more, the surrogate
test was validated. A wrong conclusion here would be to accept
validity if the surrogate endpoint was an independent determinant
of the true endpoint, but not of the treatment modality. It
is to be hoped that this paper will affect the validity of
future clinical trials constructed with surrogate endpoints.
[Back to top]
Clinical Trials: How to Assess Confounding and Why
So
Ton J. Cleophas and Aeilko H. Zwinderman
Background: In large randomized controlled trials
the risk of random imbalance of the covariates is mostly negligible.
However, with smaller studies it may be substantial. In the
latter situation assessment and adjustment for confounders
is a requirement in order to reduce a biased assessment of
the treatment comparison.
Objective: In the current paper three methods for
confounding assessment and adjustment are reviewed for a nonmathematical
readership.
Methods: First method, subclassification: the study
population is divided into subclasses with the same subclass
characteristic, then, treatment efficacy is assessed per subclass,
and, finally, a weighted average is calculated.
Second method, regression modeling: in a multivariable regression
model with treatment efficacy as independent and treatment
modality as dependent variable, the covariates at risk of
confounding are added as additional dependent variables to
the model. An analysis adjusted for confounders is obtained
by removing the covariates that are not statistically significant.
Third method, propensity scores: each patient is assigned
several odds ratios (ORs), which are his/her probability,
based on his/her covariate value of receiving a particular
treatment modality. A propensity score per patient is calculated
by multiplying all of the statistically significant ORs. These
propensity scores are, then, applied for confounding adjustment
using either subclassification or regression analysis.
Conclusions: The advantages of the first method include
that empty subclasses in the treatment comparison are readily
visualized, and that subclassification does not rely on a
linear or any other regression model. A disadvantage is, that
it can only be applied for a single confounder at a time.
The advantage of the second method is, that multiple variables
can be included in the model. However, the number of covariates
is limited by the sample size of the trial. An advantage of
the third method is, that it is generally more reliable and
powerful with multiple covariates than regression modeling.
However, irrelevant covariates and very large / small ORs
reduce power and reliability of the assessment. The above
methods can not be used for the assessment of interaction
in the data.
[Back to top]
Targeting Ion Channels for New Strategies in Cancer
Diagnosis and Therapy
Matteo Conti
A number of experimental evidences in cell biology and pharmacology
demonstrate that cancer cells, as well as stem and other proliferating
cells, exhibit ion channels expression, ion conductances and
electric properties very different from that of resting cells.
These peculiar properties are functionally involved in cancer
pathogenesis. A systematic approach in recognizing these peculiarities
in cancer cells and tissues could be very useful in the prognosis
and molecular classification of various types of cancer. From
a therapeutic perspective, inhibitors and modulators of ion
channels have been demonstrated to be able to impair cancer
cell proliferation in vitro and, in a few studies,
to counteract cancer progression in vivo. Early attempts
to modulate cellular ion conductances with electromagnetic
fields are also present in the literature and represent interesting
starting points for future research. In clinical oncology,
the relevance of ion channels is not currently recognized
thus clinical applications are missing. But, in the light
of the data here reviewed, preclinical and clinical experimentation
in this field appear not only rational but also strongly advisable.
[Back to top]
Ethanol Metabolism and Effects: Nitric Oxide and its
Interaction
Xin-Sheng Deng and Richard A. Deitrich
Ethanol (EtOH) in alcoholic beverages is consumed by a large
number of individuals and its elimination is primarily by
oxidation. The role of nitric oxide (NO) in EtOH's effects
is important since NO is one of the most prominent biological
factors in mammals. NO is constantly formed endogenously from
L-arginine. Dose and length of EtOH exposure, and cell type
are the main factors affecting EtOH effects on NO production.
Either acute or chronic EtOH ingestion affects inducible NO
synthase (iNOS) activity. However it seems that EtOH suppresses
induced-NO production by inhibition of iNOS in different cells.
On the other hand, it is clear that acute low doses of EtOH
increase both the release of NO and endothelial NOS (eNOS)
expression, and augment endothelium-mediated vasodilatation,
whereas higher doses impair endothelial functions. EtOH selectively
affects neuronal NOS (nNOS) activity in different brain cells,
which may relate to various behavioral interactions. Therefore,
there is an excellent chance for EtOH and NO to react with
each other. Effects of EtOH on NO production and NOS activity
may be important to EtOH modification of cell or organ function.
Nitrosated compounds (alkyl nitrites) are often found as the
interaction products, which might be one of the minor pathways
of EtOH metabolism. NO also inhibits EtOH metabolizing enzymes.
Furthermore, NO is involved in EtOH induced liver damage and
has a role in fetal development during EtOH exposure in pregnancy.
The mechanisms underlying these effects are only partially
understood. Hence, the current discussion of the interaction
of EtOH and NO is presented.
[Back to top]
Clinical Efficacy and Effectiveness of Ursodeoxycholic
Acid in Cholestatic Liver Diseases
Davide Festi, Marco Montagnani, Francesco Azzaroli, Francesca
Lodato, Giuseppe Mazzella, Aldo Roda, Anna Rita Di Biase,
Enrico Roda, Patrizia Simoni and Antonio Colecchia
Ursodeoxycholic acid (UDCA), previously used for cholesterol
gallstone dissolution, is currently considered the first choice
therapy for many forms of cholestatic syndromes. Many mechanisms
and sites of action have been proposed for UDCA, but definitive
data are still missing regarding the key points of its efficacy
and optimal dosage in order to achieve a sustained clinical
effect. Among the suggested mechanisms of action of UDCA,
changes in bile acid pool composition, hepatocyte membrane
protection, immunomodulatory effects and bicarbonate-rich
hypercholeresis have been extensively studied. However, recent
evidence indicate that UDCA is a potent intracellular signalling
agent that counterbalances impaired biliary secretion, inhibits
hepatocyte apoptosis and protects injured cholangiocytes against
toxic effects of bile acids. It is clear that the relative
contribution of these mechanisms to the anticholestatic action
of UDCA depends on the type and stage of the liver injury.
Available clinical evidence suggest that UDCA treatment has
to be initiated as early as possible and that higher doses
could be more efficacious in inducing and maintaining clinical
remission of cholestatic diseases. The future availability
of UDCA derivatives will possibly enhance the chances to effectively
treat chronic cholestatic diseases.
[Back to top]
Open Questions on Bioequivalence: An Updated Reappraisal
Antonio Marzo
During the last thirteen years, the author has investigated
a relevant number of bioequivalence trials, for the approval
of generics, which in the Mediterranean area show an increasing
business trend. In his activity the author has faced several
problems, most of them not considered in operating guidelines,
defined “open questions on bioequivalence”. They
deal with the most appropriate procedures to adopt in case
of studies on drugs with long half-lives, of ethics problems,
high data dispersion, endogenous substances, presence of active
metabolite(s), prevalent metabolites and reversible metabolism,
very low plasma concentrations, multiple peak phenomenon,
titre differences, polymorphic metabolism, stereogenic atoms.
The relevance of a pilot trial, mainly for modified-release
formulations, and the problem of frauds are discussed as well.
These open questions are discussed in the present review taking
into account EU and US FDA guidelines, current literature
and personal experience. In most cases suitable approaches
are suggested.
Appropriate procedures should be planned and defined in the
study protocol and extensively discussed in the final report.
An appropriate approach to the “open questions”
is a requisite to achieve a clearly defined bioequivalence/bioinequivalence
conclusion.
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