Introduction to Module 5: Assessment of Drug Effects

Introduction to Module 5: Assessment of Drug Effects


Thank you for joining this session. It’s an introduction to the assessment of
drug effects for the NIH Principles of Clinical Pharmacology. This module, module five, the assessment of
drug effects, has five sessions: biomarkers of drug effects, pharmacodynamic and pharmacokinetic
modeling of data, disease progression models, role of pharmacodynamics in drug development,
and Immunotherapeutics. Well, if the definition of clinical pharmacology
is the science of drug action in humans and their optimal clinical use in patients, then
that begs the big question, how can we measure drug effects in humans? Well, that large question can be broke down
into two main subcomponents. The first is, how can we measure the effects
of humans on drugs? When a drug is administered to a patient,
what does the human body actually do to the drug? The second is, how can we measure the effects
of drugs on humans? What are the clinical effects and how can
we infer those from certain other indirect measurements? To illustrate the importance of the measurement
of the effect of drugs, I thought I’d talk about how common drugs are. There are nearly 12,000 — about a third of
which have been approved. Most of those drugs are small molecule drugs,
like acetaminophen or ibuprofen — about 10,000. There are almost 1,700 biotechnology related
drugs or protein related drugs. And there are over 9,000 targets for those
drugs that have been approved. And that’s an average of two and a half drug
targets per drug. And it ranges up to as many as 10. About two out of every three people in the
United States have used a prescription drug within the past 12 months. And drugs account for about nine percent of
the overall health spending. So, it’s important that we be able to measure
the effects of drugs accurately. The first topic relates to biomarkers in health. When we administer a drug to a patient, we
need to be able to measure something accurately and objectively, and reliably. And that is called a biomarker. And ideally a biomarker should be reflective
of the actual biology going on in the human or the disease itself. Examples of biomarkers include: sweat chloride,
which can be used in the diagnosis of cystic fibrosis; blood glucose, which can be used
for diagnosis and monitoring of patients with diabetes; blood pressure, again, diagnosis
and monitoring in patients who have hypertension; and the CEA, which can be used in the diagnosis
of patients with colon cancer, and fibrinogen which can be used to determine the prognosis
of patients with COPD. Pharmacokinetics is defined as the study of
the time course of drugs in the body. And the main components are referred to as
ADME, and that includes absorption, distribution, metabolism, and excretion. Clinical pharmacokinetics is the application
of pharmacokinetic principles to the use of drugs in patients. Pharmacokinetics requites the ability to accurately
and precisely measure the concentration of drugs in either blood, tissues, or any other
bodily fluid. Commonly, pharmacokinetics are influenced
by the root of administration. If the drug is given by intravenous route,
it has a quick effect. If it’s given by oral or topical administration,
it may have a delayed onset of effect. And it’s important to be able to characterize
the quantity of the drug in the system at varying times. Measurements can be made after administering
either a single dose of the drugs or multiple doses of a drug, throughout a range of doses,
including low, medium, and high. This is an example of an arbitrary drug. On the Y-axis you have drug concentration,
and the X-axis time. And you can see the line shows the drug being
absorbed into the body, being distributed and eventually eliminated by the drug by metabolism
or excretion. And that drug has an area under the plasma
concentration curve that is reflective of the overall effect of the drug. Pharmacodynamics then, is the relationship
between drug concentration at the site of action and the resulting effect. It includes the time course and the intensity
of the therapeutic effect, or the adverse effect. And we can address the potency of a given
drug within a class of similar drugs. Commonly, pharmacodynamics is exhibited by
a typical S-shaped curve. At low concentrations — measured on the X-axis
— we can have a given effect. And that’s measured on the Y-axis. At very low concentrations, you can see that
there is no appreciable effect. And then as the concentration increases, that
effect increases dramatically, until a plateau is hit. And one of the common parameters that we use
is the effective concentration in 50 percent of the individuals — or 50 percent of the
effect and the EC50. What is the role of pharmacodynamics in drug
development? Drug development is a natural extension of
pharmacodynamics. The first step is proof of mechanism, which
is the effects of a drug on a given drug target. And the second step is the proof of concept,
which is the consequences of the drug in the body. All phases of drug development use pharmacodynamics,
from the pre-clinical, to the clinical, and the post-marketing effects of the drug. Disease progression models have been dramatically
improving over the last one to two decades. And these models involve math to quantitatively
determine the change in a disease’s status over time. We can compare the natural progression of
the disease with a treatment effect and we commonly use biomarkers and we link them with
pharmacokinetic and pharmacodynamic data. Pharmacodynamics can be used to improve drug
development productivity. And finally, we can use disease progression
models in the application of cost-effectiveness and genome-wide analyses. Here is an example of a hypothetical drug
for disease modeling. The y-axis has the disease severity and the
x-axis has time. And the solid line depicts the increase in
severity of the disease over time. The dotted line as to do with a drug effect
that might temporarily reduce symptoms and you can see the symptoms improve when the
drug is given and then revert back to baseline when the drug is taken away. A second option for a drug effect on disease
severity is where a drug modifies a given severity of the disease and you can see that
by the dashed line having a decreased slope compared to the natural course of disease. Immunotherapeutics also called biologic response
modifiers — or biologics — have a dramatically increased role in healthcare in the past recent
years. They can be used to treat disease by altering
the immune system. And there’s two effects that can occur. One is by activating the immune system or
enhancing or amplifying it when we’re trying to get rid of something bad, like cancer cell. And the other effect is suppressing or reducing
or blocking the immune system when it is in overdrive function. And that would be an inflammatory condition
like rheumatoid arthritis or inflammatory bowel disease or psoriasis. The advantage of immunotherapies is that they
have the potential for greater effectiveness or decreased side effects because they are
target to a narrow therapeutic role. We can combine the immunotherapies with traditional
treatments and, again, have improved effectiveness or decreased toxicity. The downside is that these drugs may be associated
with their own unique adverse effects. Here’s an example of a monoclonal antibody. The top portion of the antibody is the variable,
or Fab region. And that is what binds to the antigen. The fixed portion, or Fc region, of the antibody
does not change. These monoclonal antibodies may inhibit inflammatory
reactions like cytokine release, interleukin release, and they may inhibit cellular function
as well — and activation, like T-cells, macrophages, fibroblasts, and osteoclasts. Common examples of immunotherapeutic drugs
include CAR T cell therapy for cancer, cancer vaccines, which can prevent cancers or treat
them after they occur, viruses that can be used to treat cancers, and anti-tumor necrosis
factors drugs used in inflammatory conditions, and finally the checkpoint inhibitors, which
have dramatically increased over the last few years. So, in summary it is imperative that we accurately
measure drug effects. And we can measure drug effects either directly
or indirectly. Assessing drug effects plays an essential
role throughout the drug development process. Thank you for attending this session.

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