PCSK9 Inhibitors – Lipid Control

by Pravin Shukle, MD

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    00:01 Okay, let's go on to the PCSK9's. So this is a whole new world for you guys because you are entering medicine at a time that's really very exciting. These class of drugs which are monoclonal antibodies are changing the entire landscape of medicine. You are getting drugs that no longer follow the normal rules of pharmacology. So all of that stuff we've been learning about, binding curves and everything has changed. I very much encourage you to watch the immunology lecture through Lecturio because it's going to explain how these drugs are working in different systems. Let me explain to you why these drugs are so exciting using cholesterol control as an example. But remember this stuff, this monoclonal antibody stuff, it's in every system, whether it's dermatology, or rheumatology, or bone mineral physiology. The immune globulins and the monoclonal antibodies are so exciting as to make me want to see what happens in the next 15 years no matter what.

    01:05 This is really exciting stuff. The only downside of these agents is they are really hard to pronounce. So if you'll forgive me, I'm going to use the trade names instead of the generic names because I can barely get my mouth around them.

    01:20 Praluent, Repatha and bococizumab which does not have a trade name yet as of the time of making this lecture are monoclonal antibodies that are humanized. So if you look at the suffix of these drugs it will tell you what percentage are humanized and not. And if it ends in 'umab' then you know that it's fully humanized. These are not drugs in a typical sense. These are immuneglobulins that are binding to your target. And they are not cleared by the liver or the kidney. They are cleared by the reticuloendothelial system. So this is a linear, non-specific clearance pathway. It doesn't follow normal pharmacological rules. The other way that we get rid of these drugs from the body is what's called target mediated disposition. Once again normal pharmacology rules don't apply. They are a non-linear, saturatable clearance pathway. The large size of this molecule means that there is no clearance by the kidney. The large size of these molecules mean that they generally will not cross the blood brain barrier or the blood uterine barrier. And also, the whole idea behind pKa and whether or not it's protonated or not is completely mute because polarity doesn't really apply to a molecule this big. And in comparison to how big these molecules are to regular drugs. If you are to imagine a regular drug to be the size of my thumb, then the monoclonal antibody would be roughly the size of a building. So they are very large sized molecules and like I said, normal pharmacology rules don't apply. Let's talk about the baseball glove analogy again. So I'm gonna do the baseball glove analogy without looking at the picture here and then we are gonna look at the picture together. So remember that this baseball glove is the LDL receptor. It catches LDL just like a baseball. It's internalized into the cell, and when it's in the cell it will either release the LDL to get broken down and go back up to the surface to catch more, or sometimes it gets clipped shut so that it as well as the LDL particle are broken down. Now, if it and the LDL particle are broken down, then there is a signal inside the cell to make more LDL. Let's talk about that clip. That clip is PCSK9. That clip's job is to bind LDL and the baseball glove together so that both of them will get broken down. And what ends up happening is you have more LDL receptor expression. So let's now look at our diagram here. So LDL binds to the receptors on the surface of the cell.

    04:23 That's our baseball. The LDL receptor and the LDL itself are internalized through receptor mediated phagocytosis or endocytosis.

    04:35 The LDL is then broken down in the endosomes. Normally the LDL goes back up to the surface. Meanwhile, the PCSK9 gets released into the bloodstream. The PCSK9 clips on to the LDL-receptor complex. The PCSK9, which is the ligand. The LDL receptor and the LDL are all degraded at the same time. Now you have less LDL at the surface of the cell, right. The LDL receptor recycling is reduced. More PCSK9 means less LDL receptors. Now, monoclonal antibodies attach to that PCSK9 molecule and block PCSK9 from doing it's job, right. This allows more LDL receptor expression and clearance from the blood.

    05:41 So that means there are now, because there is no more clips, all of the baseball gloves are going to the surface and all of the baseball gloves are now catching LDL. So that in medical term we say, more LDL receptor expresion and more LDL clearance from the blood. Now, remember that intracellular cholesterol concentrations are high.

    06:04 So the hepatocyte itself is going to manufacture less cholesterol. The end result is that there is less intracellular cholesterol production. Number 2, there are more LDL receptors to reduce the blood levels of LDL.

    06:21 And number 3, there is markedly lower LDL levels. Okay, that's pretty complicated stuff but that just goes to show you that these new drugs are really quite effective. The beauty of these drugs is this. Number 1, side effects are almost 0.

    06:40 The only major side effect we see are the injection site reactions. Number 3, when we talk about how much we use them most of the agents are given once a week or once every 2 weeks. So it involves one injection once a week or once every 2 weeks.

    06:57 And there may be one in the future that's going to be a once a month injection. So we are really quite excited about this.

    07:04 The other thing that's quite interesting and I can't believe i'm saying this is that we actually have monoclonal antibodies in multiple therapeutic areas. So instead of having people take 5 or 6 drugs at the same time, we can now have them come in to the offices once or twice a month and get their injections at multiple times, and I imagine we'll be doing studies looking at multiple injection sites in the future, and there is no reason why we should'nt be able to give an injection for their cholesterol, an injection for their rheumatoid arthritis, an injection for their skin disease all at the same time. That's why these drugs are so exciting. Some of the monoclonal antibody therapies, not in cholesterol but in other areas, are actually given once every 3 months.

    About the Lecture

    The lecture PCSK9 Inhibitors – Lipid Control by Pravin Shukle, MD is from the course Cardiovascular Pharmacology.

    Included Quiz Questions

    1. Clearance by the reticuloendothelial system is by a linear, non-specific pathway.
    2. Clearance via the target mediated drug disposition pathway is non-saturable and non-linear.
    3. They require glucuronidation in the liver before they are biologically active.
    4. They are usually excreted by the kidney.
    5. They are affected by drugs that affect the CYP450 system.
    1. Injection site reactions
    2. Elevation of hepatic transaminases
    3. Increased hepatic triglyceride levels
    4. Increased risk of colon cancer
    5. Increased risk of renal failure
    1. Less intracellular cholesterol production
    2. Increased degradation of LDL receptor complexes.
    3. Elevated levels of PCSK9
    4. Very low levels of intracellular cholesterol
    5. Decreased LDL receptor recycling.

    Author of lecture PCSK9 Inhibitors – Lipid Control

     Pravin Shukle, MD

    Pravin Shukle, MD

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