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Phases of Drug Development – Absorption and Distribution | Pharmacokinetics (PK)

by Pravin Shukle, MD
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    00:01 Okay, let's talk about something a little bit different. Let's talk about phases of drug development. So this mythical pharmaceutical company called Gargantua Pharmaceuticals has developed an eye drop that can give humans X-ray vision.

    00:16 So far rats have been able to see cheese through solid walls. And dogs can see chew toys through sheets of plywood.

    00:24 Okay sounds like a fun drug. The chief executive officer comes to you and wants to know what is the next phase of drug development. Is it phase 1, 2, 3 or 4. In order to answer this question let's go through what the different phases are.

    00:39 So when we are testing a drug we talk about the pre-clinical phase. This is where we do in vitro testing in little test tubes and little beakers. And then we go on to animal testing and then animal safety testing. That's the preclinical phase.

    00:53 Then we move on to the clinical phase which is in human, phase 1, 2, 3, and 4. When we talk about in vitro testing we're really talking about various chemical parameters. We measure pKa, we measure tissue stability, tissue binding.

    01:08 Whether or not a drug in sensitive to light or not. Whether or not it will actually leech into the plastic of a pill container.

    01:15 All kinds of things are tested at this stage of development. We do environmental testing because we want to know if this drug is dropped into the sewer, is it going to cause damage to fish and to wildlife. And we do stability testing.

    01:31 Whether it's hot temperatures, if you leave the drug on the dash of your car, or if you accidentally let it freeze in a cold climate. Animal testing is always tested on at least two species. We test acute toxicity and subacute toxicity.

    01:50 And then we do animal safety testing which is a pharmacologic profile and reproductive toxicity. Let's move on to some pregnancy risk categories because that's going to be relevant in our next part of our lecture. Category A risk drugs have controlled studies. They are done in women and they fail to show any kind of harm in the first trimester which is embryogenesis. So these are very very safe drugs. Category B drugs have animal reproduction studies. They have shown no fetal risk in the animals and no evidence in human women that there is going to be any fetal risk. If there are adverse events in animals they are not confirmed in women. That makes it a category B drug. A category C drug shows animal reproduction studies showing teratogenic or embryocidal effect on foetus and no controlled studies on women. There is no studies on women available, that's what defines category C but we've seen harm in animals. Category D drugs show both animal and human studies where there is definitive human risk and life threatening. The drug is only used in life threatening situations.

    03:00 And category X are drugs where sometimes the risk outweighs the benefits. Sometimes the benefits outweigh the risk but category X drugs are generally drugs that we don't want to use and nowadays we generally have other drugs that we can choose from. So let's move on to the clinical phase. The clinical phase can be phase 1, 2, 3 or 4. In phase 1 studies we do dose response relationship in healthy male volunteers. In the United States we can do anywhere from 20-200 volunteers. In the United Kingdom and in Canada it's generally between 80 and 200 volunteers. You may use volunteers in smaller numbers in cancer patients as well. In terms of evaluation of patients with disease, now in phase 2 studies they are much larger, 100-250 patients. Sometimes they are even larger than that. There is usually with a placebo controlled arm and pharmacokinetic and pharmacodynamic data is collected at this point. Once this information is definitely analysed and definitely verified, independantly we move on to phase 3 trials. So phase 3 trials are the big ones that we always talk about. There is generally a placebo arm. Generally it's compared against oral therapy, pardon me older therapy. We monitor for rare forms of toxicity and adverse events. And if that phase 3 study is successful, the drug company will submit a new drug application or NDA to the FDA. In Canada, that NDA goes to the health protection branch.

    04:42 And in the European Union there are multiple agencies like the EMEA or CHMP, or sometimes national organizations or subnational organizations that will be able to evaluate this for them. Phase 4 refers to post marketing surveillance. Manufacturers are always required globally to inform the FDA at regular levels and inform the regulatory agency within whatever country that they are operating in. It depends upon you. So you as a physician need to notify the drug company if you see an adverse event. I personally have filled out probably 2000-3000 phase 4 forms over the course of my career. So it's an important part of development of drugs and you play a very important part. So let's go back to our question. We were asking whether or not the next phase of development is phase 1, 2, 3 or 4. Well, clearly Gargantua Pharmaceuticals finished or completed much of their animal trials. They are ready for human trials. So the answer is going to be phase 1. And in case you are wondering, yes that's my dog Tucker in the picture and he always lies like that each morning and watches me get dressed.

    05:55 I hope you enjoyed this lecture and if you have any questions you can certainly email us. There are more lectures to follow and we're gonna as lots of questions and we're gonna make you much better at writing your exam.


    About the Lecture

    The lecture Phases of Drug Development – Absorption and Distribution | Pharmacokinetics (PK) by Pravin Shukle, MD is from the course Pharmacokinetics and Pharmacodynamics.


    Included Quiz Questions

    1. The drug has been tested on pregnant animals with no evidence of harm, but there are no studies looking at women.
    2. The drug has shown no evidence of harm in the first trimester.
    3. The drug has been shown to cause harm in pregnant women.
    4. The drug was tested on animals with evidence of teratogenicity, but there are no studies in women.
    1. The drug will now be tested through multi-centered trials with and without the disease evaluating for effectiveness in comparison to older therapy and for rare adverse reactions.
    2. The drug is now ready to be used in the marketplace, with physician surveillance to evaluate for adverse events.
    3. The drug has undergone testing in a trial of 200 healthy volunteers and will now be tested in patients with disease, with pharmacokinetic and eutectic studies to determine various chemical and pharmacological parameters.
    4. The drug has undergone in vitro studies, has passed in vivo studies on two animal species, and is now ready for a study in healthy male volunteers without disease.
    1. Testing on healthy human volunteers
    2. Environmental testing
    3. Chemical parameter determination
    4. Toxicity testing in rats
    5. Stability testing
    1. No controlled studies have been shown in women.
    2. No fetal risk in animals.
    3. No harm has been shown in women in controlled studies.
    4. Only in vitro testing has been performed at this stage.
    5. Teratogenic effect shown in animals.
    1. Phase 4
    2. Phase 3
    3. Pre clinical
    4. Phase 1
    5. Phase 2

    Author of lecture Phases of Drug Development – Absorption and Distribution | Pharmacokinetics (PK)

     Pravin Shukle, MD

    Pravin Shukle, MD


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