Drug Discovery and Development

Drug Discovery and Development

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.  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. 

how the body handles the drug, clears it, distributes it, and other factors. 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. This slide depicts the concentration versus time curve, which is involved in the pharmacokinetic studies. 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 event  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 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. 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. 

The goal of this is to enhance the elimination from the body. 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 by biologics, I mean antibodies or antibody drug conjugates. And so, when an antibody or a nanop 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. 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. 

Therapeutic index.

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 to100 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 redline. 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. 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. 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. They are highly interactive. 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. When it makes the response steeper or less steep. And so, these are important concepts that need to be performed for all drugs.