Overview of clinical pharmacology in cancer 1

Hello, I'm Jill Kolesar and today's lecture is the Overview of Clinical Pharmacology in Cancer.

Today, we will cover some background information, focus on pharmacokinetics, pharmacodynamics, pharmacogenetics and finalize it up with a summary.

What I'd like to talk to you about now is an overview of drug development. When a new chemical entity is discovered, first a great deal of pre-clinical research is required to be done. There is synthesis and purification of the compound and that's followed by animal testing, both short-term and long-term animal testing for toxicology. There are also a number of clinical pharmacology studies that are performed at that time. So probably, the most important one is to get an idea of the metabolism, so the drug is incubated with hepatocytes or using other model systems to determine if it's metabolized by a particular cytochrome P450 enzyme or if it induces or inhibits those enzymes as well. The IC50 is determined and so pharmacology really does play a fairly large role in the early testing of a new drug. After all the testing has been completed, the next thing that happens is an IND or Investigational New Drug application is submitted to the FDA. At that time, the FDA can determine whether the drug is going to go on to clinical testing or not, and if it is going on to clinical testing, the initial phase clinical testing is going to be phase I. The goal of a phase I study is to determine the maximum tolerated dose and to really come up with a dose that's going to be recommended in phase II. Phase I studies are typically conducted in patients that have advanced refractory cancers, and they don't always have a therapeutic endpoint, although some patients do benefit. The drug then goes on to phase II if there's a small efficacy signal and phase II will typically be in a specific population of only one disease type. What we're seeing even more commonly now is phase IIs are actually conducted in patients with a particular type of mutation. So we're seeing targeted therapies being approved based on just phase II data. Other drugs, though that are not as targeted do go on to phase III studies, and in the phase III study, the new therapy is compared to standard of care. Clinical pharmacology does play a role in all phases of this testing. In between phase I and phase II, there are usually food effect studies to determine if a drug can be administered with or without food, that doesn't form the package labeling. There are also studies that are conducted in special populations, which we'll talk a little bit about more. These special population studies are for patients who have renal and hepatic dysfunction and to determine what the dose would be in those special populations. There are also a number of drug interaction studies that are conducted in the phase II stage of drug development, and we'll talk about all of these and their study designs in a little bit more detail as the talk goes on. Once clinical testing is completed, the next thing that happens is an NDA or New Drug Application is submitted to the FDA. At that point, the FDA just makes a decision whether the drug can be approved or not. And they can approve it with no changes, they can send it back for additional studies or they can just approve it.