What Physiologists Working in Industry Do Liaison with Industry Committee (LWIC) American Physiological Society Objective
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Liaison with Industry Committee (LWIC)
American Physiological Society
The purpose of this presentation is to 1) inform you about the responsibilities and types of work a Physiologist performs as a member of the pharmaceutical, biotech, or nutritional industry; and 2) describe some of the primary personal attributes necessary to succeed in this environment.
Activities are listed from first discovery principles (hypothesis generation and
testing) to clinical trials and submission of an NDA (New Drug Application)
using molecular and genomic approaches including genetic
association studies in humans, knockout and transgenic animals,
engineered tool compounds to identify or confirm a biochemical
questions: does the enzyme, receptor, channel, etc… play a role in
the physiological or disease process? Is the target of interest be
activated/inactivated in this process?
hypothesis in simple systems such as isolated proteins and/or
cell-based systems. These assays may often use high-throughput
or multiplexed (multiple readouts) platforms.
questions such as: does the cell, tissue, or animal model resemble
the human condition? Is the model valid? (i.e. does the
pathophysiology respond to current pharmacotherapies?)
questions such as does the compound affect enzyme, ion channel,
or receptor activity? Does the compound affect a specific signaling
pathway? Does the compound affect genetic regulation (expression)
of the target?
the organism does to drug” and studies are designed to address
questions such as: what is the maximal plasma concentration of drug
after dosing and when does this occur? how much drug gets to the
tissue of interest and how widely is the drug distributed in the body?
how quickly is the drug cleared after dosing?
“what the compound does to the organism” and studies are designed
to address questions such as: is the biochemical target affected by the
compound and to what extent? Is the tissue of interest affected?
to address questions such as: does the compound modify disease
progression in vivo (i.e. prevention model)? Can the compound
regress the disease (treatment model)? How does the efficacy of
the compound compare to existing pharmacotherapies or potential
organ function with ability to carefully control dose, duration, and
exposure to compound (e.g. isolated working heart, isolated perfused
kidney, isolated blood vessel, brain slice, etc…)
evaluation of unexpected clinical events (utilization and identification of
appropriate biomarkers to track mechanistic or pathophysiological
responses to agent).
questions such as: what is the therapeutic index of the compound?
What is the incidence of adverse events in major organ systems (e.g.
cardiovascular, renal, gastrointestinal, respiratory, CNS) at multiples
(3x, 10x, 30x) of therapeutic plasma concentrations of the compound?
Industry scientists have many responsibilities beyond benchwork…
research to various professionals to enable business and scientific
Investigational New Drug; NDA: New Drug Application) to the Food &
Drug Administration (FDA)
To be successful in discovering and developing a new drug, you must
participate in a process that requires concerted efforts by many people
across many departments and disciplines. Specific attributes are required
to succeed in this fast-paced environment…
timely scientific responses to discovery projects and business
internal/external scientists to assure access to current and innovative
technologies and scientific advances.
huge undertaking, successful industry scientists foster a cooperative
spirit, and work well with other scientific, regulatory, clinical, and
whether one on one, in small groups, or through formal presentations.
Writing is clear, well-organized and logically developed; the audience
is taken into consideration.
experimental models to run and multiple compounds to test). Thus,
industry scientists are constantly challenged to implement new processes
to streamline procedures while maintaining rigorous standards.
necessary changes in operations or strategies; also initiates new ways
of accomplishing work.
and implement tactics to deliver results by set timelines. Leads by
appropriate actions and behaviors; inspires and guides others to
achieve corporate and personal goals.
Target discovery studies investigate disease mechanisms using molecular and genomic approaches in knockout and transgenic animals. Physiologists use these approaches to identify or confirm a role for biochemical targets in organ and organism function and dysfunction. Below: gene knockout of PKCa improves cardiac performance following pressure overload (TAC), while transgenic overexpression of PKCa impairs cardiac performance.
PKC knockout (Prkca -/-) mice have enhanced cardiac ventricular performance
Overexpression of PKC (Prkca) in transgenic mice reduces cardiac ventricular performance
Reprinted with permission from Braz et al. Nature Med 10(3), 2004
Proof-of-concept studies address whether a biochemical target plays a role in a disease process (i.e. is the target of interest activated, inhibited or differentially expressed in disease?) Physiologists use various approaches to learn whether a biochemical target is involved in disease. Lower left panel: over-expression of the cardiac enzyme, calcineurin (CN) transgenic mouse, induces cardiac hypertrophy; lower right panel: aortic-banding increases cardiac CN expression (A) and activity (B), treatment with CsA, a CN, inhibitor prevents aortic-banding induced cardiac hypertrophy (C).
Reprinted with permission from Molkentin Circ Res 87, 2000
Reprinted with permission from Lim et al. Circulation 101, 2000
In vitro efficacy studies employ assays utilizing simple systems (e.g. isolated proteins and/or cell-based systems). These preparations allow Physiologists to carefully control experimental conditions and compound concentrations while measuring and comparing responses and behaviors of large numbers of compounds. Below: a classical competition curve utilizes radioligand binding techniques to evaluate the ability of compound Y to compete for receptor subtype binding, in turn generating affinity and potency data.
Enalapril blocks the blood pressure response to Angiotensin I: The
mechanism of action is the antagonism of angiotensin converting enzyme
% inhibition of the mean arterial pressure
response to Angiotensin I bolus
(300 ng/kg, IV)
Ultimately, drugs developed through the discovery process must be able to modify disease progression and outcome. Physiologists develop models of disease for drug discovery, and must have an thorough understanding of normal and pathologic ranges of functional parameters. A valid disease model must involve many of the critical biochemical pathways and display many clinical findings of the human disease state. Below: Surgical instrumentation and induction of chronic pacing-induced heart failure.
Pacing-Induced HF and Recovery
Pharmacokinetic studies characterize how the body handles a compound. Physiologists
work alongside Medicinal and Bioanalytical Chemists to determine if a compound is orally bioavailable and will achieve adequate plasma and tissue exposure and duration prior to undertaking an efficacy or chronic disease modification study. Below: Oral administration of Compound X (10 mpk) exhibited good fractional bioavailability (F% = 54%) and plasma half-life (t1/2 = 6 hours).
Counts per Minute
10 mpkPhysiologists in Industry:Pharmacodynamic Studies
Pharmacodynamic studies characterize the effects of a compound on the body. Certain enzymes are activated (e.g. phosphorylated) or modified (e.g. glycosylated) in disease processes. For example, to determine if a compound will inhibit an enzyme of interest, Physiologistsdetermine whether enzyme phosphorylation and kinase activity are suitable pharmacodynamic indices for compound activity. Below: intraperitoneal administration of a physiological stimulus dose-dependently increased enzyme phosphorylation and kinase activity, providing a model to assay compound activity against this enzyme’s activity.
Western Blot – Phosphorylated Enzyme
Immunoprecipitation Kinase Assay
* p < 0.01 vs. vehicle
* p < 0.01 vs. vehicle
p-TXXX / Total enzyme
Ex vivo studies evaluate integrated organs and organ systems from normal and diseased organisms. These preparations allow Physiologists to carefully control experimental conditions and organ compound exposures while measuring and comparing functional responses in normal and diseased organs. Below: an isolated working heart preparation allows careful control of preload, afterload, heart rate, and compound exposure.
Cardiac Systolic Performance Endpoints
LV Systolic Pressure mmHg
LV End Diastolic Pressure mmHg
Left Atrial Pressure mmHg
Aortic Mean Pressure mmHg
Max +/-dP/dt mmHg/sec
Peak Pressure mmHg
Time to Peak Press (TPP) msec
Diastolic Function Endpoints
1/2 Relaxation Press (1/2 RP) mmHg
1/2 Relaxation Time (RT1/2) msec
(RT1/2) / (1/2 RP) msec/mmHg
Drugs developed through the discovery process must show efficacy in modifying disease progression and outcome. Physiologists develop models of disease for drug discovery, and are required to have a thorough understanding of normal function as well as the pathology of disease states. Last, models of human diseases for drug discovery must be amenable to standard pharmacotherapies. Below: Effects of varying delay (7 day vs. 30 days post-MI) of ACE inhibitor treatment on a) survival, b) cardiac hemodynamics, and c) morphology after myocardial infarction (MI).
ACEi 30d post-MI
ACEi 7d post-MI
Reprinted with permission from Mulder et al. Circulation 95, 1997
Blood and/or urinary biochemical markers that are correlated to disease severity allow tracking of disease progression and regression following drug therapy. Physiologists a) develop disease models that have biomarker profiles similar to those observed in human disease, b) evaluate biomarker responses to standard and novel therapeutic agents, and c) develop assays to quantify biomarkers. Below: Kaplan-Meier survival curve for mortality and morbidity in human heart failure patients based on plasma brain natriuretic peptide (BNP) concentrations. Thus, plasma BNP is associated with disease severity and may be used in place of more expensive and time-consuming assays.
Reprinted with permission from Anand et al. Circulation 107, 2003