Today, I’ll provide an overview of the field of clinical pharmacology, as well as the fundamental principles of pharmacokinetics and their clinical applications. Traditionally, the course has focused on the theoretical foundations of substance use, growth, and assessment. We do not consider this to be a course in therapeutics, but of course, there will be relevant examples of applications of clinical pharmacology in therapeutics. We will discuss general principles that are applicable to both old and new drugs. There is a textbook that has been used for this course for a number of years, Principles of Clinical Pharmacology.
The lead editor is Dr. Arthur J. Atkinson, Junior.
An outline of what I would like to cover today.
The general scope of the discipline, some brief historical notes. We will talk about what do clinical pharmacologists engage in as professionals. We will emphasize the topic of variability in drug response as an area of great interest in our field. Also, adverse drug reactions and their impact both in terms of drug development and clinical use of drugs. And finally, a brief overview of drug development. So, let’s move on, then, and
The general scope of the discipline
Define pharmacology as the study of drugs and biologics and their actions in living organisms. Generally, when we talk about medications, we think about small molecules, chemical agents. When we talk about biologics, we think about big molecules, peptides, and antibodies.
The most fundamental concept of our field is that clinical pharmacology is the study of human drugs and biologics. The field really encompasses the scope of drug discovery, drug production, drug use, and drug control.
In clinical pharmacology, we aim at advancing therapeutics In humans with mechanistic understandings of drug actions —
This is an area termed pharmacodynamics — and also drug disposition, and that is, of course, the subject of pharmacokinetics. Now, of course, you know the definition of translational sciences and how much it has been stressed over the last decade or so. Essentially, we speak about the information that has been gained in animal or clinical disease models, or by ex vivo experiments in human tissues, or in vivo studies in healthy or diseased humans, which are then converted into successful care for patients.
Clinical pharmacology is a translational discipline that is important for the production of drugs and human therapy.
Now, a little bit of history concentrating on the pioneers of American clinical pharmacology.
I’m talking about Dr. Harry Gold and Dr. Walter Modell at Cornell University, and this is a partial list of their accomplishments and fundamental contributions. Introducing the double-blind clinical trial design in 1937; initiating the Cornell Conference on Therapy a couple of years later; and in the early ’50s, analyzing digoxin effect kinetics to estimate the absolute bioavailability as well as the time course of the chronotropic effects of digoxin.
We’ll come back to this example later. And in 1960, they created the journal Clinical Pharmacology and Therapeutics, which is now, of course, the leading journal in the field. Now, at the NIH, we can remember Dr. Albert Sjoerdsma, who led the experimental therapeutic branch of the National Heart Institute from 1958 to 1971.
He educated individuals of the stature of Lou Gillespie, John Oates, Leon Goldberg, Richard Crout, Ken Melmon, and many others who later became pioneers in the discipline. Their studies focused on serotonin and carcinoid syndrome, pheochromocytoma, antihypertensive medications, and much more.
What are the professional goals of clinical pharmacologists?
They are interested in the discovery, development, evaluation of new medicines and how their use is regulated by the Food and Drug Administration in the United States and other regulatory agents in other countries. They are also interested in optimizing the use of existing medicines and often finding new indications for old drugs. However, as I discussed in our initial outline, a crucial area of interest for clinical pharmacologists is the definition of the basis for variability in therapeutic and toxic drug reactions, and this is an example of exposure to two antidiabetic drugs, pioglitazone on the left side of the slide and metformin on the right. And we’re looking at drug exposure in terms of the region under the time-to-time plasma concentration curve. And this is the AUC, Area Under the Curve, which has been normalized to a 15-milligram dose of pioglitazone and a 500-milligram dose of metformin, and has also been normalized to 70 kilograms of body weight for a human patient. And you can see the great variability that we see in drug exposure, both in females and males, in both of these antidiabetic agents.
This is one of the difficulties that clinical pharmacologists face in seeking to understand the basis for this variability in medication exposure and how it can affect the therapeutic actions of the drug. Another source of drug exposure variability may be related to underlying genetic variants. In this case, we use the example of nortriptyline, a tricyclic antidepressant that has been in use for many years, and the effect of polymorphism of cytochrome P450 II D6.
Now, let’s move to another big field of interest in clinical pharmacology;
Adverse drug reaction
Some drug toxicity may be controlled and may be permissible based on a risk/benefit ratio, but other adverse reactions and toxicity due to their existence and severity are not acceptable, and these medications must either be excluded from clinical use or used with extreme care and commitment to significant and close patient monitoring. We need to understand, of course, that risk/benefit is subjective, depending on the medication and the condition that we wish to treat. It is not the same to consider potentially severe toxicity to a medication designed for the treatment of hypertension, a disorder that requires lifelong therapy, Compared to, say, cancer treatment, a condition that is potentially fatal over the short term and that needs very intensive treatment with a mixture of medications of very severe toxicity. Again, risk/benefit is subjective, and we need to understand the medication in question and the illness that we wish to treat. Now, again, in terms of genetics as it may relate to serious drug toxicity, there is now a disorder or circumstances, if you will, where the underlying genetic variant may predispose individuals to serious drug toxicity. Here are the examples of HLA B5701. Individuals carrying this HLA variant are at very high risk of hypersensitivity to abacavir. Abacavir is a medication used in the treatment of HIV and AIDS infections and any patient is first screened for this variant, HLA B5701, before starting treatment with abacavir. If they have the variant, they cannot be treated with that drug; an alternative must be sought. The next example we present here is that of HLA B1502, predisposing to extreme carbamazepine-induced Stevens-Johnson syndrome.
This is a severe cutaneous adverse drug reaction that can potentially be fatal. Thus, once again, the underlying genetic variants impart a predisposition to serious drug toxicity. Another indication of unacceptable drug toxicity is torsades de pointes.
Now, look at the metabolic transformation of terfenadine in humans and the production of terfenadine carboxylate as a metabolite. Very interestingly, this metabolite is active. It also has this antihistamine pharmacological action, and it’s also a non-sedating antihistamine, but terfenadine, which is marketed as Allegra, does not have the risk of a drug-induced arrhythmia like torsades de pointes. And this again brings us to consider and remember
The Importance of studying drug metabolism
To also assess whether metabolites are also pharmacologically active or are otherwise inactive ones, whether transformation has taken place. Let me bring you the example of thalidomide, again, in terms of unacceptable drug toxicities, but actually with a very interesting history, as I will show you in a moment.
Thalidomide was introduced in the 1960s as a sedative and actually was prescribed as an anti-nausea medication to pregnant women. Unfortunately, in many countries — although not in the U.S. because thalidomide was not approved in the United States, and actually was not allowed to enter the market at the time because of the discovery of some severe toxicity to unborn children due to prenatal drug exposure. This led to an epidemic worldwide of phocomelia, children born with severe defects in terms of their limbs. And of course, this is a very unfortunate outcome of the use of that drug in pregnant women. Now, there were consequences to this thalidomide crisis.
For one thing, the United States Congress approved the Kefauver Harris amendment in 1962 that instituted new and more strict FDA regulations to establish whether drugs were, on the one hand, effective but safe. And the process has been modernized over the years, but, again, emphasizing safety and demonstrating efficacy of drugs before they’re allowed into the market. The Institute of Medicine and the National Academy of Sciences began to review therapeutic claims at that time, and also more research on the causes of adverse drug reactions was encouraged. And the National Institute of General Medical Sciences has set up a number of clinical pharmacology centers in the United States to further develop rational drugs in order to provide the scientific basis for drug use in clinical medicine, and again, unfortunately, as a result of this big thalidomide crisis. Our discipline is also eminently interested in the discovery and evaluation of new medicines.
We’re starting with the discovery of drugs, and this is a phase in itself that we’re going to discuss in depth in another session of this course.
Then we have preclinical, meaning animal testing of candidate drugs, and eventually clinical evaluation to demonstrate safety in humans and whether or not the drug is effective in a given clinical condition. But then we also have post-marketing studies. Once the drug enters the market we continue to evaluate for the possibility of rare adverse drug reactions that were not discovered in the pre-approval stage, and also performing studies in special populations like the elderly and children. Now, this is a schematic of pre-marketing drug development. You see here the face of preclinical development. We have animal models; we have assay development. We study pharmacokinetics and pharmacodynamics in animals. We will, of course, begin to research animal toxicity in the short and long term if the medication is intended for prolonged use. And once a package of information has been established that suggests that the candidate drug might, in fact, be promising, an investigational new drug application, the IND will be submitted with the Food and Drug Administration or other regulatory agencies, and then we will begin the process of testing drugs in humans.
Typically considered as Phase I:
First dose in human studies; dose escalations to assess tolerance.
Phase II, when we do the proof of concept studies, treating patients with the condition that may benefit, potentially, from the drugs. And Phase III, the large randomized clinical trials comparing the new drug to a placebo or to a previously established therapy. And that then leads to the submission of a new drug application, or NDA, where the sponsor asks the regulatory agents to review this body of evidence and request approval for marketing the drug and to begin using the drugs in clinical practice. One way to look at the phases of drug development is with the “learn and confirm” paradigm.
The late Dr. Lou Scheiner and his colleagues advocated this approach. Phase I and Phase II are the learning phases of drug development. Phase III is the confirmatory phase, and Phase IV, again, is the post-marketing phase, but learning continues, focusing on rare adverse drug reactions and special populations, if required.
This is an area where the National Institutes of Health and other academic investigators have been very interested in, and that has to do with finding new biological targets and new therapeutic indications for old drugs. What are the potential advantages of this approach?
Well, for one thing, it may shorten drug development time.
We already know a lot about the safety of the drug, and we also have data in terms of the human pharmacokinetic behavior of the drug. And drug repurposing then, and this is the concept of Dr. Austin at NCATS, is illustrated in this fashion.
Now, as a rule, we have a drug screening process involving thousands of compounds, and the whole process can take 10 years between identifying the target agent and performing all the preclinical and clinical phases of drug development that may lead to drug approval. What if, then, by re-using a much smaller number of drugs that have been used for other indications—the period of drug development could perhaps be reduced to a few years? Now, this is ideal, but conceptually, again, it’s really necessary. And we have examples of a variety of medications that have been re-used, and very interestingly, we’ve got it again:
Extremely toxic and prohibited in pregnant women, but still, through clinical observation by a physician in the 1960s, it became a very useful agent to lead—or, rather, to treat a leprosy complication called erythema nodosum leprosa. Again, a medication that was otherwise prohibited from marketing is now being used in a clinical condition such as erythema nodosum leprosa.
Years later, the drug was actually tested in the condition of multiple myeloma—again, a type of cancer—this time, via targeted drug production. In any case, these are now two authorised indications of the FDA. This an immunomodulatory agent; marketing is done under a very special and very restricted distribution program referred to as System for Thalidomide Education and Prescribing, but a very good example of drug repurposing. And in this slide, I show you a list of drugs that were approved originally for a different indication, but now are FDA-approved for indications that, for example, for sildenafil, include pulmonary hypertension.
Lamotrigine being used for bipolar disorder; and so forth. So, again, repurposing as a viable and potentially very important way to look at finding new indications for old drugs. Now, let us move on to the second step of our discussion today and introduce you to the basic principles of pharmacokinetics and its clinical applications. We’re going to talk about the apparent volume of delivery and the clearance parameters. These are two parameters which we call the primary pharmacokinetic parameters. Then we’re going to discuss first-order kinetics. The vast majority of medications that we use in clinical medicine follow the trend of drug elimination first-order kinetics, although there are exceptions. And that will lead us to explore drug removal kinetics with Michaelis-Menten.
The quantitative analysis of the time course of drug absorption, drug distribution, drug metabolism, and excretion or elimination from the body.
Schematically, here we prescribe a dose or administer a dose of medication to a human subject, then we need to wait for the process of absorption to take place so that the drug can be carried, typically from the gastrointestinal tract to the systemic circulation.
The drug in plasma may circulate as a free drug, but it may also bind to plasma proteins such as albumin. And again, you have this reversible balance between the plasma-free drug and the protein-bound drug. The level of protein binding varies enormously, depending on the drug in question.
Drug removal will then take place, however, of course, the delivery of drugs from the plasma compartment will take place. The drug may actually spread to most tissues, and you may notice that the drug is unspecifically bound to tissues, but where we are really interested, it is the delivery of the drug to its pharmacological location, what is called the bio phase, and of course, the study of receptor binding, and ultimately, the effect of the drug that we’re looking for.
Again, drug metabolism may contribute to elimination, and renal excretion is a pathway for the elimination of drug metabolites, but also a significant pathway for the elimination of the parent drug itself if the biotransformation is incomplete or does not actually take place. And finally, this is where we want to test the factor of adherence. Physicians prescribe medicine to patients; eventually, patients determine whether or not to take their prescribed medication.
Monitoring compliance is essential to the production of drugs.
If you are evaluating the efficacy of the drug you want to know that patients are actually taking the medication as prescribed before you make a statement like “The drug does not work.” Well, we need to have rigorous control for adherence in the context of clinical drug development.
what are the uses of pharmacokinetics?
Pharmacokinetics provides the basis for rational dose selection in the therapeutic field. It is important for the production and assessment of new drugs. We need to know how the drugs are absorbed, to what degree they are absorbed when administered orally, where the medication is distributed, and again, how the drug is removed and what the rate of drug removal is.