WEBVTT

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Welcome back to The Deep Dive. Today, we're going

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to be tackling the fascinating world of drug

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discovery. Oh, very cool. Specifically, that

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initial spark of an idea. OK. And the journey

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from, you know, wouldn't it be cool if? Right.

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To actually pinpointing a target for a new medicine.

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It's a bit like setting out on an expedition,

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you know? You know, you want to discover something

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valuable. Right. But first, you have to choose

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the right terrain to explore. OK. I like where

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this is going. Yeah. So we're talking about the

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very early stages, even before scientists start

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tinkering in the lab. Exactly. Our source material,

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pharmaceutical product development, in vitro.

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in vivo correlation, right, emphasizes the crucial

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role of unmet medical needs and deep biological

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insights in shaping these initial steps. You've

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piqued my curiosity. Good. What kind of needs

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are we talking about and how do they spark ideas

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for new drugs? Well, imagine a disease with no

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effective treatments or a treatment that's effective

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but comes with a laundry list of side effects.

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Oh gosh. Those are glaring needs that scream

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for innovation. So it's like finding a problem

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that's begging for a solution. Yeah. A medical

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mystery waiting to be solved. Precisely. Okay.

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Let's take digoxin. Okay. A heart failure medication.

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Scientists knew it was effective, but also that

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its absorption varied wildly depending on the

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formulation. Interesting. That unmet need for

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consistent delivery -fueled research into how

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particle size affects digoxin's dissolution and

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bioavailability. Fascinating. So recognizing

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those unmet needs helps set the stage for drug

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discovery. Yes. But how do scientists actually

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go from a broad need to a specific target for

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a new medicine? Think of it like choosing the

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right lock to pick. Okay. First you need to understand

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how the lock works, right? Okay, I'm following.

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Okay. So in this case, the lock is the disease

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mechanism and the key is the drug. Brilliant

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analogy. Thanks. Scientists need to delve into

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the intricate biological pathways behind a disease.

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Pinpointing the molecules or processes that are

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going haywire and contributing to the problem.

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That's how they find potential drug targets.

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It sounds like detective work at the cellular

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level. Yes. Looking for those. molecular culprits.

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It absolutely is. Take the antifungal medication

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grusofolvin. It was initially plagued by poor

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absorption. Oh wow. By understanding that the

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drug itself wasn't the issue. But rather, it's

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low solubility. Scientists were able to create

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a micronized formulation that dramatically increased

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its effectiveness. So it's not just about finding

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a target. It's also about understanding the target's

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quirks and how a drug might interact with it.

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Exactly. Once potential targets are identified,

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they need to be rigorously evaluated. Remember,

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not all targets are created equal. So what makes

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a good drug target? What are scientists looking

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for? in this molecular lineup? Think of it as

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a three -legged stool. Okay. Drugability, safety,

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and efficacy. Okay, break that down for me. What

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does it mean for a target to be drugable? A drugable

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target is one that can be effectively modulated

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by a drug molecule. Okay. Imagine trying to open

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a lock with a key that's the wrong shape. It

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just won't work. Oh, I see. Right. So the grug

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needs to be able to fit the target and have a

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real impact on its activity. Precisely. And of

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course, safety is paramount. Right. Interfering

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with the target shouldn't cause unacceptable

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side effects. You don't want to fix one problem

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only to create a host of new ones. Right. It's

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like making sure the key doesn't accidentally

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unlock a bunch of other doors and cause chaos.

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Exactly. What about efficacy? Efficacy means

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that hitting the target should have a real meaningful

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impact on the disease. Okay. The key needs to

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actually open the right door and lead to the

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desired outcome. Finding a target that checks

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all those boxes? drugable, safe, and efficacious.

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That's gotta be like finding a needle in a haystack.

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It's one of the biggest challenges in drug development,

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no question. Scientists are constantly pushing

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the boundaries using cutting edge technologies

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and insights to sift through potential targets

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and identify the most promising candidates. Wow.

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Yeah. So finding those ideal targets is like

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a high stakes treasure hunt with scientific ingenuity

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as the map. I like that analogy. But let's dive

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a little deeper into this idea of drugability.

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Okay. What are some of the factors that determine

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whether a target can actually be modulated by

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a drug? That's a great question. Thanks. One

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key factor is the target's structure. Think of

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a drug molecule like a puzzle piece. Okay. And

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the target, like a puzzle board. Right. For the

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drug to work, it needs to fit snugly into a specific

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spot on the target. So the target needs to have

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a binding site. Yes. A pocket or a groove where

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the drug can latch on. Exactly. Okay. And that

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binding site needs to be accessible to the drug.

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Right. If it's buried deep inside the target

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molecule, the drug might not be able to reach

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it. It's like trying to fit a key into a lock

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that's hidden behind a wall. Right. No matter

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how perfectly the key matches the lock, it's

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useless if you can't get to it. That's a perfect

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analogy. Another important factor is the target's

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function. Ideally, you want to target a molecule

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that plays a key role in the disease process,

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something that's essential for the disease to

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thrive. So it's like finding the weak link in

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the chain, the Achilles heel of the disease.

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Precisely. And you want to make sure that hitting

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that target will have a significant impact on

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the disease, ideally stopping it in its tracks

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or at least slowing it down. But how do scientists

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actually figure out which targets are worth pursuing?

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Right. It seems like a daunting task sifting

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through all those molecular suspects. It is a

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challenge. But thankfully, scientists have a

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growing arsenal of tools and technologies to

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help them. OK. One powerful approach is high

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throughput screening. High throughput screening.

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What's that? Imagine a giant library filled with

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millions of potential drug compounds. Oh, wow.

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Each one slightly different from the next. High

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throughput screening allows scientists to test

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these compounds against a target. in a very rapid

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and automated way. So it's like speed dating

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for drugs. Uh -huh, yeah. Trying to find the

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perfect match for the target. That's a fun way

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to think about it. Yeah. And once they've identified

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some promising hits, they can then start to optimize

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those compounds, tweaking their structure to

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improve their binding affinity, their potency,

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and their overall drug -like properties. It sounds

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like a process of refinement. Yes. Starting with

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a rough diamond and carefully shaping it into

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a brilliant gem. That's a beautiful analogy.

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And of course, throughout this entire process,

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safety is always top of mind. Scientists are

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constantly evaluating the potential toxicity

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of these compounds, making sure they're not causing

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harm while trying to do good. So it's a delicate

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balancing act, trying to maximize efficacy. while

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minimizing risk. Exactly. And it's a process

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that requires incredible precision ingenuity

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and a deep understanding of both biology and

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chemistry. Okay, so we've talked about unmet

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medical needs, the characteristics of good drug

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targets, and the tools scientists use to find

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and refine those targets. But our source material

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also mentioned something called the biopharmaceutics

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classification system, BCS. How does this fit

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into the picture? The BCS is a brilliant system

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that helps us understand how a drug's properties

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influence its journey through the body, specifically

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how well it gets absorbed from the gut into the

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bloodstream. So it's like a roadmap for drug

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absorption, helping scientists predict how a

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drug will behave based on its inherent characteristics.

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Exactly. The BCS classifies drugs into four categories

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based on their solubility and permeability. Solubility,

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as we've discussed, is how well a drug dissolves

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in fluids, and permeability is how easily it

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crosses biological membranes. Right, those are

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two key hurdles a drug needs to overcap to get

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into the system. Absolutely. Class I drugs are

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the superstars. High solubility and high permeability.

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They dissolve easily and zip across membranes

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without a hitch. So those are the drugs that

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have an easy time getting absorbed. No special

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tricks needed. You got it. Great. Then we have

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class II drugs, which have Low solubility, but

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high permeability. They can cross membranes readily,

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but their absorption is limited by how well they

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dissolve. So it's like having a sports car with

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a flat tire. It has the potential for speed,

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but it needs a little help to get rolling. That's

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a great analogy. Thanks. And this is where formulation

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strategies become crucial for class II drugs.

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OK. Scientists can use techniques like particle

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size reduction or special excipients to boost

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their solubility and improve their absorption.

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So it's like giving that sports car a new set

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of tires allowing it to reach its full potential.

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Precisely. OK. Then we have class III drugs.

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OK. High solubility but low permeability. They

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dissolve well. But they have a harder time crossing

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those biological barriers. So it's like having

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a key that fits the lock but can't quite turn

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it. It needs an extra push to unlock the door.

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Exactly. And in this case, scientists might explore

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strategies like permeation enhancers, substances

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that can temporarily increase the permeability

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of membranes, giving those class III drugs a

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helping hand. It's like lubricating the lock,

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making it easier for the key to turn. Perfect

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analogy. OK. And finally, we have the class IV

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drugs. OK. low solubility and low permeability.

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They face an uphill battle on both fronts, making

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them the most challenging to work with. It's

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like having a rusty key that can't quite fit

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a stubborn lock. You need a whole toolbox of

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tricks to get that door open. That's a great

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way to visualize it. Developing effective formulations

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for class IV drugs often requires a combination

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of strategies. And even then, achieving adequate

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absorption can be tricky. So understanding the

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BCS classification is like having a cheat sheet

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for drug absorption. Yeah. Helping scientists

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anticipate potential hurdles and design strategies

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to overcome them. Absolutely. OK. It's a powerful

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tool that helps guide the development process

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and ensures that scientists are choosing the

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right approaches for each drug. Right. Ultimately

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increasing the chances of getting effective treatments

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to patients. OK. So we've explored how unmet

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needs spark drug discovery. Right. the intricate

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process of target selection, and the importance

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of understanding drug properties through the

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BCS. But our journey isn't over yet. There's

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one more fascinating area we need to delve into,

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in vitro, in vivo correlation, or IVIVC. IVIVC,

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the bridge between the lab bench and the human

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body. It's like having a crystal ball. OK. That

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helps us predict how a drug will behave in the

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real world based on its performance in laboratory

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tests. That sounds incredibly powerful. But how

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does it actually work? How can we connect the

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dots between what happens in a test tube and

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what happens in a living, breathing person? It

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all starts with dissolution testing, which we've

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touched upon already. Remember, dissolution is

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the process of a drug dissolving in a fluid,

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like those found in our gastrointestinal tract.

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It's a crucial step for absorption, as a drug

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needs to dissolve before it can enter the bloodstream.

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It's like making a cup of tea. The tea leaves

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need to infuse into the hot water before you

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can enjoy the flavor. Exactly. And just like

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you can control the strength of your tea by adjusting

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the brewing time. Scientists can assess the rate

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and extent of drug dissolution using carefully

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controlled laboratory tests. So these tests help

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us understand how quickly and completely a drug

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dissolves outside of the body. Yes. Giving us

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clues about how it might behave inside. Precisely.

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And here's where IVIVC comes in by comparing

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dissolution data from these in vitro tests with

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data from in vivo studies like clinical trials.

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We can build a predictive model. So it's like

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finding a pattern. Yes. A correlation between

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how a drug dissolves in the lab and how it gets

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absorbed in the human body. You got it. OK. And

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the stronger that correlation, the more confident

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we can be in predicting a drug's performance

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based on its dissolution profile. This has huge

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implications for drug development. OK, I'm seeing

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the potential. So how does IVIVC actually help

00:12:38.759 --> 00:12:41.860
scientists create better medicines? In several

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ways. First, it can help optimize drug formulations.

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By understanding how dissolution influences absorption,

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scientists can fine -tune the composition of

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a drug product to achieve the desired release

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profile. So if a drug is dissolving too quickly

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or too slowly, they can tweak the formulation

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to get it just right. Exactly. Cool. IVIVC can

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also play a role in reducing the need for certain

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clinical trials. Really? If we have a strong

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correlation between in vitro and in vivo data,

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some bioequivalence studies might be waived.

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bioequivalent studies. Those are the ones that

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compare generic drugs to brand name drugs. Yes.

00:13:18.179 --> 00:13:19.899
To make sure they work the same way, right? That's

00:13:19.899 --> 00:13:23.600
right. And if we can demonstrate bioequivalence

00:13:23.600 --> 00:13:27.279
through dissolution testing alone, it can save

00:13:27.279 --> 00:13:29.740
time and resources, ultimately getting those

00:13:29.740 --> 00:13:32.320
generic medications to patients faster. That's

00:13:32.320 --> 00:13:35.110
a win for everyone. less expensive medications,

00:13:35.330 --> 00:13:38.110
and a faster path to market. Exactly. Are there

00:13:38.110 --> 00:13:41.529
any examples of how IVIVC has been used to improve

00:13:41.529 --> 00:13:44.149
real -world drugs? Absolutely. Remember that

00:13:44.149 --> 00:13:46.330
heart failure medication digoxin we talked about

00:13:46.330 --> 00:13:49.909
earlier? Its bioavailability can vary significantly

00:13:49.909 --> 00:13:52.909
depending on how quickly it dissolves. By establishing

00:13:52.909 --> 00:13:56.269
an IVIVC model, scientists were able to develop

00:13:56.269 --> 00:13:58.970
a formulation with more consistent dissolution,

00:13:59.450 --> 00:14:01.370
leading to more predictable therapeutic effects.

00:14:01.629 --> 00:14:05.110
So IVIVC helped create a more reliable and effective

00:14:05.110 --> 00:14:08.889
treatment for heart failure patients. Yes. That's

00:14:08.889 --> 00:14:10.769
incredible. It's a testament to the power of

00:14:10.769 --> 00:14:12.830
understanding drug properties and their impact

00:14:12.830 --> 00:14:15.629
on the human body. Wow. And, you know, as we

00:14:15.629 --> 00:14:18.409
wrap up this deep dive. Yeah, I'm struck by the

00:14:18.409 --> 00:14:20.950
intricate web of knowledge that underpins drug

00:14:20.950 --> 00:14:23.470
development. I know what you mean. We've journeyed

00:14:23.470 --> 00:14:26.370
from unmet needs to target selection. Right.

00:14:26.470 --> 00:14:29.009
From the complexities of drug properties to the

00:14:29.009 --> 00:14:32.700
predictive power of IVIVC. Uh -huh. It's a remarkable

00:14:32.700 --> 00:14:35.399
process that blends scientific ingenuity with

00:14:35.399 --> 00:14:38.080
a profound commitment to improving human health.

00:14:38.259 --> 00:14:40.519
It truly is. Wow. And at the heart of it all

00:14:40.519 --> 00:14:44.320
is the desire to alleviate suffering to extend

00:14:44.320 --> 00:14:47.960
lives and to empower people to live healthier

00:14:47.960 --> 00:14:50.139
and more fulfilling lives. So the next time you

00:14:50.139 --> 00:14:53.139
take a medication... Remember the incredible

00:14:53.139 --> 00:14:55.620
journey it took to get there. Yes. From the initial

00:14:55.620 --> 00:14:58.159
spark of an idea to the rigorous testing and

00:14:58.159 --> 00:15:00.600
refinement, it's a testament to the boundless

00:15:00.600 --> 00:15:03.179
potential of human curiosity and the unwavering

00:15:03.179 --> 00:15:05.860
pursuit of a healthier world. Absolutely. Thanks

00:15:05.860 --> 00:15:07.259
for joining us on this Deep Dive.
