Drug development: from discovery to manufacture

Hello, my name is Michael Kinch, I'm an Associate Vice Chancellor at Washington University in St. Louis. Today, I'm going to talk about drug development from discovery to manufacture.

The key properties of a promising experimental medicine can be broadly divided into three areas: first and foremost to safety; second of all, is efficacy and third is drug ability. By far, safety is the most important consideration. Any molecule you put in the body has to be safe. The efficacy, the ability of the drug to affect the intended outcome is the second most important consideration, but it always falls behind safety. The third feature, which is known as druggability, we'll discuss in a little bit, basically reflects the practicalities of can you manufacture and administer medicine in a manner that is sufficiently practical?

In considering safety, there are two major questions. The first question is what is the impact of a single dose of a drug? What is the impact of acute exposure? In other words, once you give a medicine, is there any evidence of damage, either macroscopic or microscopic? If so, which cells and tissues are impacted? It's important to understand this after a single administration, but oftentimes and in general, medicines are given chronically, meaning that there's a repeated exposure; perhaps, you take a pill every day. In this case, it's important to understand whether there is an accumulation of the drug in the body, and if so, whether there might be certain safety considerations that arise because you have now an accumulation of this medicine. Or, perhaps, you are in a sustained manner, causing some sort of an unsafe signal to be given that is causing damage over time. In order to understand what is going on in the body over time after you take a medicine, it's important to understand its metabolism. It's important to understand that the body processes pretty much every chemical that is taken into the body. This processing generally occurs in the liver and results in what we refer to as metabolites. It's important to understand which metabolites, which breakdown products are created in the body, and does this alter the safety or the efficacy of a drug? Looking further, consider that the enzymes in the liver that are responsible for this metabolism have other jobs in the body that they normally do other than metabolizing the particular drug. As a consequence, the drug itself might alter those enzymes and change, for example, the safety or toxicity of other molecules that we encounter in day-to-day life. This is important then to understand that, for example, diet and a well-known example is the impact of grapefruit juice can sometimes change certain enzymes in the body and then change the ability of a drug or a particular drug to become toxic or to become metabolized. It's important to understand what is the impact of diet. What is the impact of other medicines and other features in the environment that we all live in that might somehow change the metabolism of a drug. As important is understanding that there are differences among populations. Some populations of people, either as a result of genetics and or a combination of genetics and environment, might mean that there is a greater safety risk for some populations than others. In understanding metabolism, it's also important to understand are these metabolites safe and do they remain effective? Does a metabolite, does a breakdown product of a drug, even if the drug itself is safe, do the breakdown products of these drugs have the potential to confer damage? Again, a question also arises is are these breakdown products still active? Do they still confer the desired efficacy? Understanding all of this metabolism is quite important to understand, again, how to administer the drug.