WEBVTT 00:00:00.000 --> 00:00:02.980 All right, let's jump right in, shall we? Today 00:00:02.980 --> 00:00:06.599 we are talking about preclinical research. Preclinical 00:00:06.599 --> 00:00:09.119 research. It's a crucial stage in drug development, 00:00:09.900 --> 00:00:12.660 but often overlooked. Absolutely. It's where 00:00:12.660 --> 00:00:16.239 scientists really figure out if a drug is safe. 00:00:16.489 --> 00:00:18.670 Right. And if it's effective. And how effective. 00:00:18.850 --> 00:00:21.050 Before it ever even gets near a human being. 00:00:21.309 --> 00:00:24.829 Yes, before it even gets into like first in human 00:00:24.829 --> 00:00:27.730 studies. Exactly. This is all the work that happens 00:00:27.730 --> 00:00:29.710 before then. And we are going to be your guides. 00:00:29.730 --> 00:00:32.369 Yeah. Through this. intricate process today. 00:00:32.390 --> 00:00:35.229 All right, buckle up. We'll uncover how researchers 00:00:35.229 --> 00:00:38.130 use a combination of lab studies. Like in vitro. 00:00:38.229 --> 00:00:41.049 In vitro. In glass. And animal studies. In vivo. 00:00:41.149 --> 00:00:44.149 In vivo to build that solid foundation. So make 00:00:44.149 --> 00:00:46.289 sure that when we do get to humans, we're doing 00:00:46.289 --> 00:00:49.189 it as safely as possible. It's like being a detective 00:00:49.189 --> 00:00:51.469 for drug molecules. It is. But let's start at 00:00:51.469 --> 00:00:54.689 the very beginning. OK. What exactly is the purpose 00:00:54.689 --> 00:00:58.020 of preclinical research? To gather information 00:00:58.020 --> 00:01:02.100 about a drug's safety and efficacy before it's 00:01:02.100 --> 00:01:04.819 given to a human, scientists want to know, how 00:01:04.819 --> 00:01:08.000 does the drug behave in a living organism? Oh, 00:01:08.019 --> 00:01:10.239 interesting. Does it reach the target tissue? 00:01:10.879 --> 00:01:15.319 How is it broken down, eliminated? And most importantly, 00:01:15.519 --> 00:01:17.799 does it cause any harm along the way? So it's 00:01:17.799 --> 00:01:19.920 a bit like a dress rehearsal. Yeah, exactly. 00:01:20.140 --> 00:01:22.379 Before the big opening night. Before we get on 00:01:22.379 --> 00:01:25.549 stage. making sure everything runs smoothly and 00:01:25.549 --> 00:01:28.390 there are no wardrobe malfunctions. For sure. 00:01:28.590 --> 00:01:31.370 And the first act of this dress rehearsal takes 00:01:31.370 --> 00:01:34.989 place in the lab. Right. With in vitro testing. 00:01:35.209 --> 00:01:37.290 In vitro, yeah, in glass. In glass. So we're 00:01:37.290 --> 00:01:39.150 talking about things that happen in test tubes 00:01:39.150 --> 00:01:42.329 and petri dishes. OK. It allows researchers to 00:01:42.329 --> 00:01:44.750 look at the drug in a very controlled environment. 00:01:45.109 --> 00:01:47.629 So they're basically testing the drug's potential. 00:01:47.629 --> 00:01:50.250 Yeah. Before introducing all the complexities 00:01:50.250 --> 00:01:53.019 of a living organism. Right. Exactly. What are 00:01:53.019 --> 00:01:55.079 some of the key tests they use at this stage? 00:01:55.180 --> 00:01:57.400 Well, one important test is called the CACO2 00:01:57.400 --> 00:02:01.140 permeability assay. CACO2 permeability assay. 00:02:01.239 --> 00:02:03.260 So permeability, we're going to talk a lot about 00:02:03.260 --> 00:02:06.140 permeability. OK. This is a specific type of 00:02:06.140 --> 00:02:09.900 cell line derived from a human colon cancer cell. 00:02:10.039 --> 00:02:12.300 Interesting. That allows us to create a model 00:02:12.300 --> 00:02:14.659 of the intestinal lining. So it's like a mini 00:02:14.659 --> 00:02:17.300 gut in a petri dish. Yeah. Basically, it's a 00:02:17.300 --> 00:02:20.280 way for researchers to see, OK, if I dose this 00:02:20.280 --> 00:02:23.979 drug orally, How well can it cross that intestinal 00:02:23.979 --> 00:02:26.439 lining and get into the bloodstream? Oh, that's 00:02:26.439 --> 00:02:29.479 so cool. Another one is called PAMPE. PAMPE? 00:02:29.879 --> 00:02:33.139 Parallel Artificial Membrane Permeability Assay. 00:02:33.360 --> 00:02:34.979 OK. I'm going to need you to break that down 00:02:34.979 --> 00:02:38.360 for me. So it's a simplified model of a cell 00:02:38.360 --> 00:02:42.180 membrane that helps researchers see how well 00:02:42.180 --> 00:02:44.500 a drug can pass through a barrier. Got it. And 00:02:44.500 --> 00:02:46.599 it has to pass through barriers to reach its 00:02:46.599 --> 00:02:49.189 target in the body. I'm sensing a theme here. 00:02:49.669 --> 00:02:52.250 Yes. Permeability. Permeability is super important. 00:02:52.349 --> 00:02:56.030 Okay. It's all about how quickly... a drug can 00:02:56.030 --> 00:02:58.729 get to where it needs to go in the body. So a 00:02:58.729 --> 00:03:01.229 drug with high permeability is going to be absorbed 00:03:01.229 --> 00:03:03.830 much more easily. Interesting. If a drug has 00:03:03.830 --> 00:03:06.069 low permeability, it's going to take a lot longer 00:03:06.069 --> 00:03:09.270 to get absorbed. So even if a drug is effective 00:03:09.270 --> 00:03:13.090 in the lab, if it has low permeability, it might 00:03:13.090 --> 00:03:15.490 not be so effective in the real world. Exactly. 00:03:15.569 --> 00:03:17.210 That's really interesting. Which is one of the 00:03:17.210 --> 00:03:19.550 reasons why in vitro testing is so valuable. 00:03:19.710 --> 00:03:22.710 It helps identify these potential problems early 00:03:22.710 --> 00:03:25.580 on. OK, so we've seen seeing the drug perform 00:03:25.580 --> 00:03:28.620 on a cellular level. On a cellular level. What's 00:03:28.620 --> 00:03:31.080 next? After the lab, we move on to animal studies. 00:03:31.580 --> 00:03:34.960 or in vivo testing. In vivo. This is a really, 00:03:34.979 --> 00:03:38.560 really crucial step because it allows us to bridge 00:03:38.560 --> 00:03:42.699 that gap between the petri dish and the complexities 00:03:42.699 --> 00:03:45.939 of a living organism. Right, because cells in 00:03:45.939 --> 00:03:48.020 a dish can only tell us so much. They can only 00:03:48.020 --> 00:03:51.259 tell us so much. In vivo testing, let scientists 00:03:51.259 --> 00:03:54.379 observe how a drug behaves in a more realistic 00:03:54.379 --> 00:03:56.180 setting. That makes sense. And to learn about 00:03:56.180 --> 00:04:00.939 things like ADME, absorption, distribution, metabolism. 00:04:00.939 --> 00:04:03.439 excretion. Like a drug's itinerary through the 00:04:03.439 --> 00:04:06.219 body. Yeah, exactly. But choosing the right animal 00:04:06.219 --> 00:04:09.139 model must be crucial. Super important. Different 00:04:09.139 --> 00:04:11.680 animal models have different strengths and weaknesses. 00:04:12.080 --> 00:04:14.840 Okay. And the choice depends on the specific 00:04:14.840 --> 00:04:17.420 drug and the research question. Interesting. 00:04:17.740 --> 00:04:21.120 So rodents are often used because they're small 00:04:21.120 --> 00:04:23.920 and easy to work with. Makes sense. while larger 00:04:23.920 --> 00:04:27.360 animals like pigs or primates might be used for 00:04:27.360 --> 00:04:30.019 studies where their physiology is more similar 00:04:30.019 --> 00:04:32.800 to humans. Interesting. Different animals for 00:04:32.800 --> 00:04:35.040 different investigations. Yeah, exactly. Okay, 00:04:35.060 --> 00:04:39.120 so we've established that a drug needs to get 00:04:39.120 --> 00:04:42.420 to where it's going in the body. Yes. But how 00:04:42.420 --> 00:04:44.560 does that actually happen? Right. I mean, when 00:04:44.560 --> 00:04:47.160 we swallow a pill, it's not like it instantly 00:04:47.160 --> 00:04:49.399 dissolves in our stomach. No, it does not. Like 00:04:49.399 --> 00:04:51.060 an elka seltzer, right? More complicated than 00:04:51.060 --> 00:04:54.089 that. Okay. The process of a solid drug breaking 00:04:54.089 --> 00:04:57.050 down into smaller pieces and dissolving in a 00:04:57.050 --> 00:04:59.649 liquid is called dissolution. Dissolution. An 00:04:59.649 --> 00:05:02.569 only dissolved drug can be absorbed into the 00:05:02.569 --> 00:05:04.970 bloodstream. OK. So dissolution is kind of like 00:05:04.970 --> 00:05:07.370 unlocking the drug's power. Unlocking the drug's 00:05:07.370 --> 00:05:10.230 power. And a key factor in how quickly a drug 00:05:10.230 --> 00:05:13.589 dissolves is its particle size. OK, now you've 00:05:13.589 --> 00:05:15.850 got my attention. Yeah. Particle size. Particle 00:05:15.850 --> 00:05:18.149 size, yeah. How does that work? Think about it 00:05:18.149 --> 00:05:21.699 like this. OK. If you want sugar to dissolve 00:05:21.699 --> 00:05:25.339 quickly in your tea, do you use sugar cubes or 00:05:25.339 --> 00:05:27.839 granulated sugar? Granulated sugar. Granulated 00:05:27.839 --> 00:05:31.360 sugar, right. Why? More surface area. More surface 00:05:31.360 --> 00:05:33.579 area? Dissolves faster. Dissolves faster, exactly. 00:05:33.759 --> 00:05:36.100 The smaller the particles, the greater the surface 00:05:36.100 --> 00:05:38.540 area and the faster it dissolves. So scientists 00:05:38.540 --> 00:05:42.209 are practically playing with... microscopic building 00:05:42.209 --> 00:05:44.170 blocks. It's kind of like that, yeah. To make 00:05:44.170 --> 00:05:46.910 sure these medicines work properly. Right. I 00:05:46.910 --> 00:05:49.290 never would have guessed that something as tiny 00:05:49.290 --> 00:05:51.569 as particle size could have such a huge impact. 00:05:51.750 --> 00:05:53.269 It's really interesting, yeah. Like it never 00:05:53.269 --> 00:05:55.170 even crossed my mind. And scientists even have 00:05:55.170 --> 00:05:57.889 an equation for it. Oh really? Called the noise 00:05:57.889 --> 00:06:00.110 Whitney equation. The noise Whitney equation. 00:06:00.170 --> 00:06:02.350 Which helps them understand and even predict 00:06:02.350 --> 00:06:05.029 how different factors influence dissolution. 00:06:05.310 --> 00:06:07.790 Okay, no need to go full chemistry professor 00:06:07.790 --> 00:06:09.949 on us. I won't, don't worry. But give us the 00:06:09.949 --> 00:06:12.470 gist. Yeah. How does this equation translate 00:06:12.470 --> 00:06:14.889 to the real world? Well, it helps us understand 00:06:14.889 --> 00:06:18.050 things like why a crushed pill works faster than 00:06:18.050 --> 00:06:21.149 a whole pill. Oh, interesting. Crushing it increases 00:06:21.149 --> 00:06:23.910 the surface area. Makes sense. Which speeds up 00:06:23.910 --> 00:06:26.589 dissolution. Okay. And scientists can even use 00:06:26.589 --> 00:06:29.769 this equation to model how a drug will dissolve 00:06:29.769 --> 00:06:32.850 and be absorbed in the body. So it's like a scientist's 00:06:32.850 --> 00:06:35.050 secret code for figuring out a drug's potential. 00:06:35.209 --> 00:06:38.550 It's a tool in their toolbox, for sure. And you 00:06:38.550 --> 00:06:41.810 mentioned some real -world examples, like Dagoxin 00:06:41.810 --> 00:06:44.329 and Grizovina. How does particle size affect 00:06:44.329 --> 00:06:48.060 them? So Dagoxin is a heart medication. And it's 00:06:48.060 --> 00:06:50.519 a great example of how particle size can make 00:06:50.519 --> 00:06:53.360 a difference in a drug's effectiveness. Studies 00:06:53.360 --> 00:06:56.379 have shown that if you can reduce digoxin's particle 00:06:56.379 --> 00:07:00.860 size, you can increase its bioavailability. Bioavailability. 00:07:00.939 --> 00:07:03.439 How much of that drug gets into the bloodstream 00:07:03.439 --> 00:07:06.759 to do its job. So in digoxin's case, smaller 00:07:06.759 --> 00:07:10.420 particles means faster dissolution, which leads 00:07:10.420 --> 00:07:13.360 to more of the drug being absorbed and ultimately 00:07:13.360 --> 00:07:17.019 a better therapeutic effect. Makes sense. is 00:07:17.019 --> 00:07:21.459 an anti -fungal medication. And it has very, 00:07:21.459 --> 00:07:24.620 very low solubility. So it's hard for the body 00:07:24.620 --> 00:07:27.500 to absorb. Right. Got it. But by reducing its 00:07:27.500 --> 00:07:30.699 particle size, scientists have been able to improve 00:07:30.699 --> 00:07:33.660 its dissolution and bioavailability. So even 00:07:33.660 --> 00:07:36.550 though it's not very soluble. Right. They found 00:07:36.550 --> 00:07:38.430 a way to make it work better. To make it work 00:07:38.430 --> 00:07:41.029 better, yeah. It's like they outsmarted the drug's 00:07:41.029 --> 00:07:43.970 inherent limitations. Exactly. This is all incredibly 00:07:43.970 --> 00:07:46.290 fascinating. It is. It really highlights the 00:07:46.290 --> 00:07:49.449 incredible ingenuity and attention to detail 00:07:49.449 --> 00:07:51.629 that goes into drug development. For sure. It's 00:07:51.629 --> 00:07:54.110 a meticulous process with many moving parts and 00:07:54.110 --> 00:07:56.029 we've only just scratched the surface. Really? 00:07:56.220 --> 00:07:58.839 There's more. Oh, yeah. This is amazing. There's 00:07:58.839 --> 00:08:00.540 a lot more to come. OK, well, I can't wait to 00:08:00.540 --> 00:08:02.339 hear all about it. You know, it's amazing how 00:08:02.339 --> 00:08:04.740 much we can learn about a drug even before it 00:08:04.740 --> 00:08:07.879 reaches a human being. Right. But all this preclinical 00:08:07.879 --> 00:08:10.959 research is really just the beginning of a much 00:08:10.959 --> 00:08:13.139 larger journey. You're talking about the journey 00:08:13.139 --> 00:08:17.420 to getting a drug approved. Yeah. for use in 00:08:17.420 --> 00:08:19.079 people, right? Well, exactly. The ultimate goal. 00:08:19.240 --> 00:08:21.779 The ultimate goal. OK. And before a drug can 00:08:21.779 --> 00:08:25.459 even be considered for human testing, researchers 00:08:25.459 --> 00:08:29.339 have to submit a ton of information to the regulatory 00:08:29.339 --> 00:08:32.039 authorities. Like the FDA. Like the FDA, yeah. 00:08:32.059 --> 00:08:35.379 OK. It's called an Investigational New Drug Application, 00:08:35.539 --> 00:08:39.620 or IND. IND. IND. It's like a drug's resume. 00:08:39.639 --> 00:08:41.820 Yeah, it is. Before its big interview. Before 00:08:41.820 --> 00:08:44.320 the big interview. Highlighting all its qualifications. 00:08:44.360 --> 00:08:47.759 All of its qualifications. It includes a massive 00:08:47.759 --> 00:08:50.659 amount of information about the drug, summarizing 00:08:50.659 --> 00:08:52.639 everything that's been learned during the preclinical 00:08:52.639 --> 00:08:55.960 phase. So like toxicology data, toxicology data, 00:08:56.220 --> 00:08:59.539 ADME properties, ADME properties, dose finding 00:08:59.539 --> 00:09:02.200 studies, dose finding studies, manufacturing 00:09:02.200 --> 00:09:05.610 details. Manufacturing details. All of it. Wow. 00:09:05.769 --> 00:09:08.029 That sounds pretty intense. It's a lot. What's 00:09:08.029 --> 00:09:10.789 the purpose of all this scrutiny? Safety. Safety, 00:09:10.929 --> 00:09:13.370 OK. The regulatory agencies want to make sure 00:09:13.370 --> 00:09:17.049 that any drug entering human trials has a solid 00:09:17.049 --> 00:09:19.669 foundation of evidence supporting its safety 00:09:19.669 --> 00:09:22.490 and potential effectiveness. So they're basically 00:09:22.490 --> 00:09:24.870 the gatekeepers. They are. Protecting the public 00:09:24.870 --> 00:09:27.590 from potentially harmful or ineffective medications. 00:09:27.830 --> 00:09:30.370 Exactly. OK. Makes sense. Yeah. So let's break 00:09:30.370 --> 00:09:32.759 down some of these key components. OK. You mentioned 00:09:32.759 --> 00:09:35.440 toxicology first. Yeah, toxicology. What kinds 00:09:35.440 --> 00:09:38.059 of studies are done to evaluate a drug's safety? 00:09:38.740 --> 00:09:41.659 So toxicology studies are designed to identify 00:09:41.659 --> 00:09:45.580 any potential red flags, any harmful effects 00:09:45.580 --> 00:09:49.539 the drug might have. And these studies are typically 00:09:49.539 --> 00:09:53.340 conducted in animals using a range of doses and 00:09:53.340 --> 00:09:55.299 durations of treatment. To really see what's 00:09:55.299 --> 00:09:57.519 going on. To assess the impact on different organs. 00:09:57.639 --> 00:09:59.299 So they're basically trying to find the drug's 00:09:59.299 --> 00:10:01.149 breaking point? Yeah, you could say that. The 00:10:01.149 --> 00:10:03.659 dose at which it starts to cause problems Right. 00:10:03.840 --> 00:10:05.679 Researchers want to know how the drug behaves 00:10:05.679 --> 00:10:09.000 at different levels of exposure, from those low 00:10:09.000 --> 00:10:12.019 doses that might be used in humans to much higher 00:10:12.019 --> 00:10:15.360 doses to reveal potential toxicity thresholds. 00:10:15.360 --> 00:10:17.440 So they're really trying to understand the full 00:10:17.440 --> 00:10:19.580 spectrum. The full spectrum, yeah. Of the drug's 00:10:19.580 --> 00:10:22.000 effects. Yes. And what kind of signs are they 00:10:22.000 --> 00:10:24.159 looking for in these studies? Looking for anything 00:10:24.159 --> 00:10:26.480 out of the ordinary. OK. So changes in organ 00:10:26.480 --> 00:10:29.940 function. OK. Liver or kidney damage, effects 00:10:29.940 --> 00:10:33.279 on blood cells. Right. Even behavioral. changes 00:10:33.279 --> 00:10:37.340 could be an indicator of toxicity. So if a drug 00:10:37.340 --> 00:10:40.960 causes serious side effects in animals, that's 00:10:40.960 --> 00:10:43.539 a pretty big red flag, right? It's a huge red 00:10:43.539 --> 00:10:46.039 flag. And that's why these toxicology studies 00:10:46.039 --> 00:10:49.460 are so important. They allow us to weed out those 00:10:49.460 --> 00:10:52.419 potentially dangerous compounds before they even 00:10:52.419 --> 00:10:55.259 get close to human testing. Got it. It's a big 00:10:55.259 --> 00:10:58.740 deal. OK, so toxicology is all about making sure 00:10:58.740 --> 00:11:01.580 a drug is safe. Right. But we also need to know 00:11:01.580 --> 00:11:05.360 that it can actually do its job right. That's 00:11:05.360 --> 00:11:07.580 where those ADME properties come in. Exactly. 00:11:07.919 --> 00:11:11.679 ADME, absorption, distribution, metabolism, and 00:11:11.679 --> 00:11:14.980 excretion. Like a drugs travel itinerary. Exactly. 00:11:15.320 --> 00:11:17.779 So how do scientists actually study these properties 00:11:17.779 --> 00:11:20.820 in the preclinical phase? They use a variety 00:11:20.820 --> 00:11:23.980 of techniques. Okay. Sometimes even radio labeled 00:11:23.980 --> 00:11:27.179 drug molecules. Wow. To track the drugs movement 00:11:27.179 --> 00:11:29.240 throughout the body. So they can literally see 00:11:29.240 --> 00:11:31.360 where it goes. They can see where it goes. That's 00:11:31.360 --> 00:11:33.720 amazing. They study how it's absorbed from the 00:11:33.720 --> 00:11:36.519 gut, how it's distributed to different tissues, 00:11:36.659 --> 00:11:39.220 how it's metabolized by the liver, and how it's 00:11:39.220 --> 00:11:42.590 excreted. So they're really following the Drugs 00:11:42.590 --> 00:11:45.129 every move they're following it. Yeah Wow And 00:11:45.129 --> 00:11:47.210 this information is crucial for understanding 00:11:47.210 --> 00:11:51.110 how the drug will behave in humans Okay, how 00:11:51.110 --> 00:11:53.490 long it will stay active in the body and what 00:11:53.490 --> 00:11:55.590 might happen to it along the way, right? So it's 00:11:55.590 --> 00:11:58.370 not just about will it work or not? Right also 00:11:58.370 --> 00:12:00.850 about understanding all the nuances of how it's 00:12:00.850 --> 00:12:02.809 interacting all the nuances. Yeah with the body 00:12:02.809 --> 00:12:05.470 That's fascinating. It also helps determine the 00:12:05.470 --> 00:12:08.070 appropriate dose for human studies. Oh, right 00:12:08.070 --> 00:12:11.610 because too high of a dose could be dangerous. 00:12:11.610 --> 00:12:14.070 Maybe very dangerous. And too low of a dose might 00:12:14.070 --> 00:12:16.429 not be effective. Might not be effective at all. 00:12:16.889 --> 00:12:20.590 So how do researchers figure out the right dose? 00:12:20.840 --> 00:12:24.000 to use in humans. Dose finding studies. Dose 00:12:24.000 --> 00:12:27.700 finding studies, okay. In animals, testing different 00:12:27.700 --> 00:12:30.360 doses. Okay. To find that optimal range. To find 00:12:30.360 --> 00:12:32.360 that sweet spot. Yeah, that sweet spot. Where 00:12:32.360 --> 00:12:34.539 the drug is both effective and safe. Exactly. 00:12:34.600 --> 00:12:36.960 Okay. And these studies also help determine how 00:12:36.960 --> 00:12:39.679 often the drug needs to be administered. Oh, 00:12:39.960 --> 00:12:42.080 okay, so like - Once a day. Once a day. Twice 00:12:42.080 --> 00:12:45.500 a day or more frequently. Wow, so many factors 00:12:45.500 --> 00:12:47.779 to consider. It's a lot. And then all of this 00:12:47.779 --> 00:12:52.200 information. toxicology, ADME, dose finding gets 00:12:52.200 --> 00:12:55.279 packaged up and sent off to the regulatory agencies 00:12:55.279 --> 00:12:58.340 in the IND. In the IND, right? Right. But there's 00:12:58.340 --> 00:13:01.200 more. Oh, there's more. We also need to understand 00:13:01.200 --> 00:13:03.860 how the drug is broken down in the body. Oh. 00:13:03.940 --> 00:13:06.240 And that's where metabolite profiling comes in. 00:13:06.639 --> 00:13:09.799 Metabolite profiling. Sounds a bit like forensic 00:13:09.799 --> 00:13:13.299 science. It kind of is. It involves identifying 00:13:13.299 --> 00:13:15.539 and characterizing the different metabolites. 00:13:15.539 --> 00:13:17.980 The breakdown products. The breakdown products, 00:13:18.039 --> 00:13:20.379 right? That are formed when the drug is metabolized. 00:13:20.539 --> 00:13:22.700 Exactly. So it's like analyzing a drug's fingerprints. 00:13:22.820 --> 00:13:24.720 Yeah, it's like that. After it's been processed 00:13:24.720 --> 00:13:27.940 by the body. Right. And those fingerprints can 00:13:27.940 --> 00:13:31.600 tell us a lot about the drug's safety and effectiveness. 00:13:32.220 --> 00:13:35.080 So it's not just about the drug itself, but also 00:13:35.080 --> 00:13:37.559 about what it becomes. What it becomes in the 00:13:37.559 --> 00:13:40.679 body. In the body. Some metabolites might be 00:13:40.679 --> 00:13:44.419 inactive, while others could be active, and contribute 00:13:44.419 --> 00:13:47.100 to the drug's overall effects. So some drugs 00:13:47.100 --> 00:13:49.419 might actually become more potent. More potent, 00:13:49.440 --> 00:13:51.679 yeah. After they're broken down. Exactly. While 00:13:51.679 --> 00:13:54.419 others might produce metabolites that have unwanted 00:13:54.419 --> 00:13:56.840 side effects. Right, so it's important to understand 00:13:56.840 --> 00:13:59.500 that whole metabolic profile. The whole picture. 00:13:59.519 --> 00:14:01.340 The whole picture, yeah. Before it moves on to 00:14:01.340 --> 00:14:03.879 human tests. It's amazing how much complexity 00:14:03.879 --> 00:14:06.600 there is. There is. In something that seems so 00:14:06.600 --> 00:14:09.159 simple like taking a pill. It seems so simple. 00:14:09.299 --> 00:14:11.259 Like a whole hidden world of chemistry happening 00:14:11.259 --> 00:14:13.840 inside us. It is. It's a fascinating process. 00:14:13.919 --> 00:14:16.220 It really is. And we're constantly learning more 00:14:16.220 --> 00:14:18.679 about how drugs interact with the body. Okay, 00:14:18.679 --> 00:14:21.759 so we've talked about toxicology, ADME, dose 00:14:21.759 --> 00:14:24.720 finding, and metabolite profiling. We have. What 00:14:24.720 --> 00:14:27.169 else goes into the IND? Well, we also need to 00:14:27.169 --> 00:14:30.190 make sure that the drug is stable. Stable? Doesn't 00:14:30.190 --> 00:14:33.330 degrade over time. OK. And that's where stability 00:14:33.330 --> 00:14:35.690 testing comes in. Stability testing. Researchers 00:14:35.690 --> 00:14:38.070 test the drug under various conditions. Like 00:14:38.070 --> 00:14:40.669 temperature, humidity, that kind of. Temperature, 00:14:40.830 --> 00:14:43.370 humidity, light. OK. To see how it holds up. 00:14:43.590 --> 00:14:46.769 So even if a drug passes all the other tests 00:14:46.769 --> 00:14:49.570 with flying colors. Right. It could still be 00:14:49.570 --> 00:14:52.590 a no go if it doesn't have good shelf life. Exactly. 00:14:52.690 --> 00:14:54.370 Yeah, makes sense. Yeah, we don't want a drug 00:14:54.370 --> 00:14:57.850 that's losing potency before it reaches the patient. 00:14:58.970 --> 00:15:01.529 And alongside stability testing, we also have 00:15:01.529 --> 00:15:04.590 early analytical development. Early analytical 00:15:04.590 --> 00:15:06.610 development. What exactly is that? This involves 00:15:06.610 --> 00:15:09.909 developing methods to accurately measure the 00:15:09.909 --> 00:15:13.110 drug in various samples, like blood or urine. 00:15:13.169 --> 00:15:15.990 Interesting. And this is crucial for understanding 00:15:15.990 --> 00:15:18.559 how much drug is present. Okay. During those 00:15:18.559 --> 00:15:21.179 preclinical studies. So they're creating tools. 00:15:21.299 --> 00:15:23.840 Yeah, they're creating tools. Subtract the drug's 00:15:23.840 --> 00:15:25.759 journey. Exactly. And make sure it's behaving 00:15:25.759 --> 00:15:28.980 as expected. Behaving as expected. It's incredible 00:15:28.980 --> 00:15:32.960 how much work and detail goes into this preclinical 00:15:32.960 --> 00:15:34.919 phase. It's a lot of work. It's like building 00:15:34.919 --> 00:15:38.519 a case. It is. For a drug's potential. Yeah. 00:15:38.639 --> 00:15:41.179 Gathering all the evidence to support its advancement 00:15:41.179 --> 00:15:43.720 to human trials. You got it. It's a rigorous 00:15:43.720 --> 00:15:46.539 process, but essential for ensuring the safety 00:15:46.539 --> 00:15:48.799 and efficacy of new drugs. Absolutely. Well, 00:15:48.820 --> 00:15:51.220 we are learning so much today. I'm glad. About 00:15:51.220 --> 00:15:53.820 all the complexities of drug development. It's 00:15:53.820 --> 00:15:56.519 really mind -boggling to think about all that 00:15:56.519 --> 00:15:59.100 goes into preclinical research. It's a lot. Before 00:15:59.100 --> 00:16:02.600 a drug even has the chance to be tested in humans. 00:16:02.899 --> 00:16:05.220 Right? It's amazing. It really highlights the 00:16:05.220 --> 00:16:07.879 dedication of all the scientists who are working 00:16:07.879 --> 00:16:10.340 to bring new medicines to the world. Absolutely. 00:16:10.440 --> 00:16:14.419 And there's one more tool that we use in preclinical 00:16:14.419 --> 00:16:16.179 research that we haven't talked about yet. OK, 00:16:16.259 --> 00:16:19.220 what's that? And that's the biopharmaceutics 00:16:19.220 --> 00:16:23.360 classification system, or BCS. Oh yeah, the BCS. 00:16:23.440 --> 00:16:25.399 The BCS. I remember you mentioning it earlier. 00:16:25.480 --> 00:16:27.399 I did. Can you remind me what that's all about? 00:16:27.539 --> 00:16:32.480 So the BCS is a way of categorizing drugs based 00:16:32.480 --> 00:16:35.799 on their solubility and permeability. Oh. Remember 00:16:35.799 --> 00:16:38.460 those two properties we talked about? Yes. Solubility 00:16:38.460 --> 00:16:42.200 is how well a drug dissolves. Right. And permeability 00:16:42.200 --> 00:16:45.059 is how easily it can pass through those cell 00:16:45.059 --> 00:16:47.190 membranes. You got it. And those are both really 00:16:47.190 --> 00:16:49.450 important. Hugely important. For a drug to be 00:16:49.450 --> 00:16:52.250 effective. For a drug to work. OK. So the BCS 00:16:52.250 --> 00:16:55.389 takes those two properties and uses them to classify 00:16:55.389 --> 00:16:57.250 drugs into four different categories. Oh, cool. 00:16:57.309 --> 00:16:59.110 OK, walk me through the categories. All right, 00:16:59.110 --> 00:17:01.210 so class one drugs are the stars of the show. 00:17:01.309 --> 00:17:04.490 OK. They have high solubility and high permeability. 00:17:05.230 --> 00:17:07.089 Which generally means they're absorbed really 00:17:07.089 --> 00:17:09.930 well. OK. Then we have class two drugs, which 00:17:09.930 --> 00:17:13.869 have low solubility but high permeability. Their 00:17:13.869 --> 00:17:16.190 absorption is often limited. by how well they 00:17:16.190 --> 00:17:19.029 dissolve. So that's something that researchers 00:17:19.029 --> 00:17:23.190 often try to optimize. Okay, so it's like class 00:17:23.190 --> 00:17:26.920 one drugs are natural born athletes. Yeah. And 00:17:26.920 --> 00:17:28.740 class two drugs need a little bit of coaching. 00:17:28.759 --> 00:17:31.279 A little coaching, yeah. To reach their full 00:17:31.279 --> 00:17:33.200 potential. To get where they need to go. OK, 00:17:33.259 --> 00:17:35.400 what about the other two classes? So class three 00:17:35.400 --> 00:17:39.440 drugs have high solubility, but low permeability. 00:17:39.539 --> 00:17:42.359 OK. Their absorption is limited by their ability 00:17:42.359 --> 00:17:44.960 to cross -cell membranes. Right. So getting them 00:17:44.960 --> 00:17:46.819 to where they need to go in the body can be a 00:17:46.819 --> 00:17:49.440 bit trickier. Yeah, I can see that. And finally, 00:17:49.640 --> 00:17:53.710 we have class four drugs. OK. The problem children. 00:17:53.890 --> 00:17:55.950 The problem children, all right. They have low 00:17:55.950 --> 00:17:58.490 solubility and low permeability, making them 00:17:58.490 --> 00:18:00.769 very challenging to develop. Right, so the BCS 00:18:00.769 --> 00:18:02.809 is like a quick reference guide. Yeah, it is. 00:18:02.869 --> 00:18:06.109 That helps researchers understand a drug's absorption 00:18:06.109 --> 00:18:08.869 potential. Right. And identify any potential 00:18:08.869 --> 00:18:11.849 challenges early on. Exactly. I like that. And 00:18:11.849 --> 00:18:14.009 you know, the BCS isn't just used by researchers. 00:18:14.089 --> 00:18:17.029 Oh, really? Regulatory agencies also rely on 00:18:17.029 --> 00:18:20.619 it. Oh, wow. To make decisions about... bioequivalence 00:18:20.619 --> 00:18:23.140 testing. Bioequivalence. Now there's another 00:18:23.140 --> 00:18:25.720 term I need a refresher on. So bioequivalence 00:18:25.720 --> 00:18:28.700 basically means that two different formulations 00:18:28.700 --> 00:18:31.799 of the same drug are absorbed into the bloodstream 00:18:31.799 --> 00:18:34.779 at the same rate and to the same extent. So they're 00:18:34.779 --> 00:18:36.660 essentially interchangeable. Interchangeable, 00:18:36.720 --> 00:18:38.940 yeah. From a clinical standpoint. Exactly. So 00:18:38.940 --> 00:18:41.140 if I take a generic version of a medication, 00:18:41.160 --> 00:18:44.180 it should work the same way as the brand name 00:18:44.180 --> 00:18:46.359 version. Exactly, because they're bioequivalent. 00:18:46.519 --> 00:18:48.420 Because they're bioequivalent. Oh, it's interesting. 00:18:48.640 --> 00:18:52.480 And for those Class 1 drugs, The stars of the 00:18:52.480 --> 00:18:55.299 show. The stars of the show with high solubility 00:18:55.299 --> 00:18:58.740 and permeability, the FDA actually allows for 00:18:58.740 --> 00:19:01.640 what's called a bio waiver. A bio waiver. What's 00:19:01.640 --> 00:19:04.200 that? So that means they don't require those 00:19:04.200 --> 00:19:08.440 extensive clinical studies to prove bioequivalence. 00:19:08.500 --> 00:19:10.819 Interesting. So in vitro dissolution testing 00:19:10.819 --> 00:19:13.359 can actually be enough. Wow. So for these well 00:19:13.359 --> 00:19:16.420 -absorbed drugs, Lab tests can sometimes provide 00:19:16.420 --> 00:19:20.099 enough evidence to show that they'll behave similarly 00:19:20.099 --> 00:19:24.180 in the body. That seems like a huge win for drug 00:19:24.180 --> 00:19:26.700 development. It is. Saving both time and resources. 00:19:26.740 --> 00:19:29.000 Absolutely. And ultimately getting those drugs 00:19:29.000 --> 00:19:31.559 to patients faster. Which is the goal. That's 00:19:31.559 --> 00:19:34.460 really cool. The BCS is a great example of how 00:19:34.460 --> 00:19:36.839 scientific understanding can be used to streamline 00:19:36.839 --> 00:19:39.400 drug development and ultimately benefit patients. 00:19:39.920 --> 00:19:42.039 Well this has been an incredible deep dive into 00:19:42.039 --> 00:19:44.700 the world of preclinical research. I agree. I 00:19:44.700 --> 00:19:46.839 feel like I've gained a whole new appreciation. 00:19:46.880 --> 00:19:49.500 I'm glad. For the complexity and importance of 00:19:49.500 --> 00:19:52.059 this stage of drug development. It's an important 00:19:52.059 --> 00:19:55.000 stage. It's amazing how much goes on behind the 00:19:55.000 --> 00:19:57.039 scenes. There's a lot that happens. Before a 00:19:57.039 --> 00:19:59.059 drug even gets to the point of being tested in 00:19:59.059 --> 00:20:00.940 humans. Yeah, most people don't even realize 00:20:00.940 --> 00:20:03.079 it's happening. It's a whole hidden world. It 00:20:03.079 --> 00:20:05.339 is. And for our listeners who want to continue 00:20:05.339 --> 00:20:08.160 exploring this world. Yeah. Here's a final thought 00:20:08.160 --> 00:20:12.279 to ponder. Imagine a world where we could perfectly 00:20:12.279 --> 00:20:16.000 predict how any drug would behave in the human 00:20:16.000 --> 00:20:18.980 body. That would be amazing. Based solely on 00:20:18.980 --> 00:20:22.299 lab and animal data. Right. What advancements 00:20:22.299 --> 00:20:24.960 in medicine would that unlock? Huge advancements, 00:20:24.980 --> 00:20:27.259 I imagine. Could this be the key to personalized 00:20:27.259 --> 00:20:30.380 medicine? It very well could be. Tailoring treatments 00:20:30.380 --> 00:20:32.779 to each individual's unique biology. It's an 00:20:32.779 --> 00:20:34.920 exciting possibility. It's an exciting possibility 00:20:34.920 --> 00:20:37.599 for sure. It is. Until next time, keep diving 00:20:37.599 --> 00:20:37.900 deep.