The Toxicologist - Society of Toxicology

isk assessment. However, unique challenges are encountered in both nonclinical
and clinical discovery and development settings when evaluating drugs with novel
mechanisms of action. In recognition of the need for a broad and integrated understanding
in the toxicology community, this symposium will blend current topics in
this field of growing interest, and present the scientific background and challenges
in the context of the emerging regulatory landscape. Speakers will discuss the translational
aspects of nonclinical and clinical findings to regulatory and scheduling
processes. Emphasis will be placed on presentation and discussion of issues, with
specific examples, that bridge these areas of interest and enhance overall awareness
of the topic.
1723 NEUROPHARMACOLOGY OF DRUGS OF ABUSE AND
IMPLICATIONS ACROSS DIVERSE DRUG DISCOVERY
PROGRAMS.
D. R. Compton. Preclinical Safety - Toxicology, sanofi-aventis U.S. Inc., Bridgewater,
NJ. Sponsor: B. Gemzik.
This presentation will provide a brief overview of the neuroscience related to the
abuse of drugs in general and with special emphasis to issues specifically cited in the
January 2010 US FDA Draft Guidance for Industry Assessment of Abuse Potential
of Drugs, such as: a) the “direct and indirect actions” of drugs on “neurotransmitter
systems associated with abuse potential” including dopamine, norepinephrine,
serotonin, gamma-aminobutyric acid, acetylcholine, opioid, N-methyl-D-aspartate,
and cannabinoid; b) receptor and/or neurotransmitter systems related to abuse
potential not cited in the guidance; and c) the application of early nonclinical data
to the development process for various categories of potential products (eg, CNStargeted
therapy, non-CNS-targeted therapy, biologics, oncologic agents); and d)
the neurotoxic effects of acute and chronic drug use or abuse.
1724 ANIMAL MODELS FOR ASSESSMENT OF ABUSE
POTENTIAL: TRANSLATION TO CLINICAL
EVALUATION.
M. J. Kallman. Covance Inc., Greenfield, IN.
The emphasis of this presentation will focus on descriptions of the preclinical models
and application of non-clinical data to clinical risk assessment of potential for
abuse. Identification of strengths and weaknesses of the primary three models (drug
discrimination, self-administration, and drug dependence/withdrawal)that are used
for these non-clinical evaluations will be presented with consideration of some of
the other models that may have utility for specific agents. The impact of species selection
for the abuse liability package based on toxicology profile, pharmacokinetics,
metabolite profile, and receptor conservation can also improve risk assessment.
1725 DESIGN AND INTERPRETATION OF CLINICAL TRIALS
EVALUATING ABUSE POTENTIAL OF DRUGS: WHERE
ARE THE GAPS?
M. Sokolowska. Grünenthal USA, Bedminster, NJ. Sponsor: B. Gemzik.
Abuse potential of drugs is evaluated based on data collected throughout the drug
development program. The clinical assessments incorporate analyses of the human
abuse potential study in addition to examination of adverse events of special interest
and aberrant behaviors observed in Phases I – III. Even though the FDA Draft
Guidance for Industry: Assessment of Abuse Potential of Drugs (Jan 2010) clarified
some aspects of these assessments, further gaps have been identified. This presentation
will focus on issues associated with the human abuse potential study design,
specifically on the selection of subjects’ population, types of controls, doses of investigational
drug and controls, as well as the selection of outcome measures and
parameters. Impact of various factors on data analysis including the contribution of
the primary versus secondary outcome measures and differentiation between statistically
significant versus clinically important differences will be examined.
Additionally, methodology to evaluate adverse events and aberrant behaviors will be
discussed.
1726 CURRENT CHALLENGES IN ABUSE LIABILITY
ASSESSMENT: DRUGS WITH NOVEL MECHANISMS OF
ACTION.
K. E. Cannon. Global Safety Pharmacology CoE, Pfizer, Inc., Groton, CT. Sponsor:
T. Brabham.
Over the recent years, there has been a marked increase in the number of drug targets
being pursued in the pharmaceutical industry with novel mechanisms of action
that have either intended or unintended central nervous system activity. These
novel targets pose unique scientific challenges for preclinical abuse liability assessments
because any underlying basis for abuse potential may be entirely unknown.
Thus, preclinical abuse assessments now present increasing challenges during the
design, analysis, and interpretation of specific behavioral studies. In addition to a
thorough evaluation of the target, several aspects of the compound profile including
its secondary pharmacology (i.e. receptor binding profile and in vitro functional
activity), in vivo pharmacodynamic effects, and pharmacokinetic profile must be
carefully integrated and assessed. These properties will shape numerous facets of the
study design, such as the model(s) to be assessed, species selection, parameters to be
measured, and choice of positive comparator, in order to provide a comprehensive
preclinical abuse liability profile of these novel mechanisms.
1727 REGULATORY AND SCHEDULING: PROCESSES AND
CURRENT CONCERNS.
M. Klein. CDER, U.S. FDA, Silver Spring, MD. Sponsor: B. Gemzik.
The Food and Drug Administration issued a Draft Guidance for Industry on
Assessment of Abuse Potential of Drugs in January 2010, in response to public
health concerns related to availability and abuse of drugs. The guidance is intended
to assist sponsors who are developing drug products with the potential for abuse on
labeling issues and scheduling requirements under the Controlled Substances Act.
Drugs with abuse potential generally include drugs that affect the central nervous
system, drugs that are chemically or pharmacologically similar to other drugs with
known abuse potential, and drugs that produce psychoactive effects such as sedation,
euphoria, or mood change. The current FDA perspective on the guidance and
related concerns will be discussed.
1728 RISK ASSESSMENT FOR PROTEINS INTRODUCED
INTO GENETICALLY MODIFIED (GM) CROPS.
B. G. Hammond. Product Safety Center, Monsanto Company, St. Louis, MO.
In 2009, there was 330 million acres of genetically modified (GM) crops planted in
25 countries. Despite rapid adoption, planting of GM crops remains controversial
in some countries. GM crops undergo comprehensive food safety assessment before
commercialization. This includes proteins introduced into the crop to achieve desired
technical effects. One of the safety questions asked is if the introduced proteins
(IP) have a history of safe use (HOSU) in food. For registration of GM crops
in Europe, if there is no reliable safety information, IP without a HOSU must be
tested in a 28 day repeat dose toxicity study. Thus we will explore appropriate information
that might resolve safety concerns for IP without a HOSU. Advances in
the field of molecular biology over the last 30 years have increased our ability to
modify the structure, stability, and activity of proteins of interest. These modified
proteins may not have a HOSU. However, absence of HOSU does not mean absence
of safety. Protein engineering and evolution studies suggest that changes in
amino acid sequences of proteins not related to those with known toxicological hazards
(i.e., toxins or allergens) will not make a protein potentially hazardous de novo.
Modifications often exert little effect on biological function, and some substitutions
are deleterious to protein structure and function. In regards to dietary risk assessment
of proteins introduced into GM crops, risk assessors have generally made the
highly conservative assumption that the IP remains functionally intact during the
processing of the crop into human food fractions. However for crops such as corn
or soy which are extensively processed, the IP that have been tested do not survive
processing functionally intact. This information could be relevant to resolving concerns
about the safety of IP that do not have a HOSU. However, if the IP is related
to known mammalian toxins, remains functionally intact after processing or is not
susceptible to digestion, then further toxicology testing may be needed.
1729 NATURE’S BALANCING ACT: EVOLUTIONARY
CHANGES IN PROTEIN FAMILIES.
J. M. Jez. Donald Danforth Plant Science Center, St. Louis, MO. Sponsor: B.
Hammond.
The dynamic interplay of an organism’s DNA, metabolism, protein structure, biochemical
function, and environment drives the evolution of new proteins. The requirement
of an organism to maintain fitness balances the changes that drive molecular
evolution of protein structure and function. The dominant genetic
mechanisms that lead to changes in protein function are: i) gene duplications; ii) divergence
of gene sequences to produce proteins with modified sequences, structures,
and functions; iii) selection of new sequences with value to organism fitness;
and, in many cases, iv) combination with other genes to continue the process of
evolution. Although DNA plasticity is central to evolution, the evolution to “new”
SOT 2011 ANNUAL MEETING 371