Introduction to Module 6: Drug Discovery and Development

Introduction to Module 6: Drug Discovery and Development


Bill Zamboni:
Hi, my name is Bill Zamboni. I’m an associate professor in the UNC Eshelman
School of Pharmacy in the UNC Lineberger Comprehensive Cancer Center. Today, I’ll be giving a lecture on the introduction
to clinical pharmacology. The objectives of this presentation are to
describe how drugs are developed and where clinical pharmacology studies are performed;
what involves pharmacokinetic studies — which is part of the absorption, distribution, metabolism,
and elimination of drugs, and how the exposures are associated with those — the definition
of pharmacodynamic studies as related to explaining key terms such as dose-response relationships,
including receptors and actions of drug targeting, and predict how individual variability in
the pharmacokinetics effect of pharmacodynamics such as efficacy and toxicity. This slide depicts the process of drug discovery
and development and the different phases of drug development. There’s pre-discovery, which is identification
of molecules. There’s the early drug development in this
part. And then, obviously, there’s preclinical drug
development, which involves pharmacology studies in animals. This will not be part of this lecture, but
just understand that a lot of the studies that we perform in clinical pharmacology,
which are involved in patients as part of clinical trials, are also performed in preclinical
studies. So, in most cases, the clinical pharmacology
studies that we’re going to be discussing are performed in phase one and phase two studies
of drugs during development. Sometimes in phase three, which are a much
larger study, and then also in post-approval studies, which are called in many cases phase
four studies. Clinical pharmacology has two basic parts,
pharmacokinetics and pharmacodynamics. Pharmacokinetics is what the body does to
the drug. So, how the body handles the drug, clears
it, distributes it, and other factors. And then pharmacodynamics is what the drug
does to the body. What are the effects of the drug on the body,
such as for efficacy, targeting, and also toxicity? So, pharmacokinetics, we can explain the pharmacology
of the drug mathematically. It’s basically the drug’s journey through
the body, and how the drug is handled by the body. There are four different basic processes to
pharmacokinetics, which is called ADME — absorption, distribution, metabolism, and elimination. When a drug is dosed, either orally or IV,
it goes into the central compartment, which is the absorption phase. It then goes into the peripheral compartment,
which is a distribution phase. And then lastly, the drug is eliminated, which
is the elimination phase. So, we’ll talk about how these studies are
performed for various drugs in development. This slide depicts the concentration versus
time curve, which is involved in the pharmacokinetic studies. Time on the X axis, concentration on the Y
axis. What we’re looking at is a term such as the
minimum effective dose or exposure and the maximum tolerated dose. This would be the therapeutic range, which
we’ll also talk about in a second. There’s important pharmacokinetic terms, such
as the Cmax or maximum concentration. There’s Tmax, which is the time of the maximum
concentration. And then area under the concentration time
curve, which is the AUC and a measure of overall exposure. And so, what we try to do in these studies
is to evaluate these different pharmacokinetic parameters and eventually see how they predict
the pharmacodynamic response. Drugs can be administered through various
routes of administration. There’s parenteral administration such as
IV, IM, or subcutaneous. Most drugs that use a parenteral administration
are IV. There’s oral administration with various formulations
such as tablets, capsules, suspensions, and liquids. There’s newer administrations such as sublingual
tablets. And then there’s also local administration. This is just a reference that can go through
different information on routes of administration. Bioavailability is a very important pharmacokinetic
term. It’s the fraction or percentage of a drug
that reaches the systemic circulation. And what I mean by that is the blood exposure. So, if you give a dose orally, it goes in
and it dissolves or breaks down into the gut. That is then absorbed into the blood and is
metabolized by the liver through first-pass effect. And then, ultimately, what gets to the blood
after the liver is what is bioavailable. So, the bioavailability here would be 30 percent. Obviously, influenced by absorption and metabolism
and bioavailability. Ultimately, the fraction absorbed is calculated
as F, which is the AUC of the desired dosage form, for example the oral, over the AUC achieved
with IV administration. So, that would be the fraction absorbed through
various formulations or dosing besides IV. There are several factors affecting the distribution. There’s factors that affect absorption — tissue
permeability, blood flow, binding to plasma proteins, which we’ll talk about in a second,
and there’s binding to additional cellular compartments, which all determine where the
drug and how fast the drug distributes throughout the body. Again, the distribution here related to the
capillary permeability. And also, a specific site of exposure is in
the brain with the blood brain barrier. And so, concentration time curves based on
distribution are different based on the different tissues. So, the exposure in the plasma, which is a
compartment within the blood, is represented by the black line. But how a drug distributes to a fat versus
lean muscle versus what gets into the brain is highly variable and drug dependent. Protein binding is also a very important,
kinetic term. It’s related to the binding of the drug to
plasma proteins such as albumin, beta-globulin, and alpha-acid glycoprotein. It’s important to remember that drugs that
are bound to these proteins have no effect. So, the term for amount of drug bound is determined
by different concentrations. There’s the free drug concentration, the protein
bound concentration, and the affinity for binding sites. So, percent of drug bound is the bound exposure
over the bound exposure plus the free exposure times a hundred. But this fraction here, which can be relatively
small, is the most important parameter. Because again, that is the active of form
of the drug. So, what could change the percent drug that
is bound? Renal failure, inflammation, malnutrition
or fasting, and also drug interactions where two drugs administered together would be binding
to the same particular protein or site. Now we’ll move to elimination as a pharmacokinetic
mechanism. And there’ll be three different types of elimination. The first one we’ll talk about is enzymatic
metabolism. The goal of this is to enhance the elimination
from the body. The enzymatic metabolism mostly occurs in
the liver by reactions that increase the water solubility. The metabolites are then secreted back into
the blood or into the bowel where they’re eliminated from the body. There are different phases of enzymatic metabolism. There’s phase one, which is making the drug
more hydrophilic, such as SIP450 enzymes would be this case. And then there’s phase two metabolism, which
involves conjugating it to also make it more water soluble so that it is eliminated. A second type of elimination is renal elimination. And there’s two different types of renal elimination. There’s filtration, which goes through the
renal glomerulus here, and its elimination through the urine. There is also secretion where, the drugs are
actively secreted through the renal tubules of certain drugs. And again, they go through elimination through
the kidney and out in the urine. So, again, two types of renal elimination
— filtration and secretion. The last type of elimination like to discuss
is a relatively new or novel form of elimination. It’s a cellular elimination via the mononuclear
phagocyte system or MPS system. And this is for complex drugs, such as nanoparticle
conjugates and biologics. And by biologics, I mean antibodies or antibody
drug conjugates. And so, when an antibody or a nanoparticle
is administered, usually IV in most cases, they reach the plasma. And then they are cleared via the kidney,
but it’s not metabolism via the kidney. It’s these active cells of monocytes and macrophages
or other phagocytic cell that are clear — that phagocytose and uptake the particles to remove
them from the blood. And this occurs in the liver and the spleen
and also through circulating monocytes in the blood. So, this is a cellular active process by which
these complex agents are removed from the circulation. An important pharmacokinetic parameter is
half-life. And by half-life, what I mean is it’s defined
as the time it takes for half the drug to be administered. So, each drug has its own half-life that needs
to be characterized. And so, as you’re giving repeated doses of
a drug — either if it’s a IV infusion and then you stop the infusion. Then the drug clears. The wash out period here and the time it takes
for half the drug to be eliminated is what we would call the half-life. And then within five to seven intervals, or
five to seven half-lives, is how long it takes the drug to be completely cleared from circulation. And also, if you’re giving repeated oral dosing,
how long it would take to get to steady state. So, again, five to seven half-lives is a very
important pharmacokinetic term. Pharmacodynamics now is the opposite. This is what the drug does to the body. It’s related to the drug’s destination or
purpose. Again, this definition of what the drug does
to the body, it involves efficacy and toxicity. We’ll talk about important terms such as therapeutic
index, sites of action, and an affinity for receptors. And so, when you give a dose or a concentration
of a drug measured in pharmacokinetic studies, the degree of response goes from zero up to
100 percent. And you get this sigmoidal curve here. Once you reach a point where giving more or
a higher concentration of drug, you get no more added effects. So, this would be the maximum effect that
can occur. And you never want to dose above that because
you don’t get added response. You just get off target effects or toxicity. And so, again, there’s different — drugs
will have different concentration versus response relationships as related to which drug would
be more efficacious. Obviously, if this drug only reaches a 50
percent response versus this drug reaches a hundred percent response, the drug represented
by the red would be more efficacious. Potency is a term, a dynamic term related
to the relative strength and response for a given dose. The effect of concentration or dose needed
to elicit half the maximum dose or response, either called the EC50 or ED50, are important
terms. And the potency is inversely related to the
EC50 or ED50, which I’ll show you here. So, for example, this would be the dose or
exposure of a particular drug. This is an elevation or treatment of pain
from zero to a hundred percent. And as the potency curve moves to the left,
that means these drugs are more potent. And as the dose or exposure responsory curve
moves to the right, these agents are less potent. Therapeutic index is a very important pharmacodynamic
term. Therapeutic index is related to the toxic
or lethal dose at 50 percent. An easier way to think about the therapeutic
index is to look at the range or distance between what is required for efficacy or what
is required for toxicity. Again, looking at the dose or exposure versus
response relationship. The efficacy curve represented by the blue. The toxicity curve represented by the red
line. The distance or interval or exposure range
between what causes efficacy and what causes toxicity is called a therapeutic index. This agent here would have a wider therapeutic
index, which is a good parameter or a good characteristic of the drug. This particular agent has a narrow therapeutic
index. So, the — which means the exposure that causes
— are associated with efficacy or causes toxicity is very close. This can be problematic for a particular drug
due to variability in kinetics and exposure from patient to patient and dynamic response. So, in pharmacodynamics there’s different
molecular mechanisms of actions. Drugs must bind to a specific site to elicit
a response, called the drug receptor site interaction. There’s many different targets for these receptors
and interactions — lipids, nucleic acids, or proteins, which are most receptors — and
many of those have not been fully characterized or identified. So, it’s a lock and key analogy. So, basically, you have a receptor. You need the drug, either drug A or drug B
to bind to the receptor to achieve a response. If drug A binds, it achieves a response or
an action that’s going on. And which one exactly happens is by affinity. And these have to do with chemical bonds and
interactions. The interactions are either reversible or
irreversible. Irreversible — but also called covalent binding. So, multiple drugs bind to multiple different
receptors to elicit a pharmacologic response. There’s different types of interactions or
agents. There’s agonists and antagonists. These are therapeutic effects — can be via
these different mechanisms. Drug interactions can also occur when an agonist
and antagonist are dosed together. The affinity for a receptor actually ends
up driving what their response will be. The amount of the attraction between the drug
and receptor, and how much drug is needed to bind to the receptor. So, it’s related to the affinity and also
drug exposures, which then gets us back to pharmacokinetic studies and responses. So, agonists bind to the receptor and cause
a measurable effect. Agonists are, again, driven by affinity and
intrinsic activity. There’s partial agonists that have affinity
and less intrinsic activity. And again, if you look at the response versus
the curve here, this would be an agonist. This would be a partial agonist representation. Here is depicted. Antagonist binds to a receptor, but no measurable
cellular or physiological change occurs. It blocks the usual receptor effect, and it
can reduce the effect of an agonist. Again, they do have affinity, but no intrinsic
activity. The different antagonists can be competitive,
or they’re binding to the same site as the agonist — can be overcome with higher concentrations,
which is represented here. And then it can also be non-competitive where
it binds to a different site besides the site where the agonist binds. And that’s depicted by the cartoon now. So, this slide depicts the summary of clinical
pharmacology, which again involves pharmacokinetics and pharmacodynamics. Kinetics are what the body does to the drug. Pharmacodynamics are what the drug does to
the body. They are highly interactive. Obviously, the kinetics affect the dynamics,
but in many cases when a system is affected by a drug, you can have a feedback loop that
may change the kinetics. And so, studies are ongoing for all drugs
at different phases of development to understand how variability in pharmacokinetic parameters
— such as absorption, distribution, elimination, and the overall exposures — affect the pharmacodynamic
response. Whether it makes the response steeper or less
steep. And so, these are important concepts that
need to be performed for all drugs. Thank you very much.

Leave a Reply

Your email address will not be published. Required fields are marked *