13 - Risk and Failure in Drug Development (S1E13)

Welcome to the deep dive. Today, we're taking
a deep dive into drug development. You might
think it's all about those eureka moments and
big scientific discoveries, but the reality is
way more complex and risky. Yeah, definitely.
It really is. The journey of a new drug, like
from a scientist's initial idea in the lab all
the way to your medicine cabinet, it's, well,
it's paved with more failures than you might
think. More failures? Really. Oh, yeah. In fact,
most drug candidates never even make it to market.
Wow. That's a pretty sobering thought. It is.
So for this deep dive, we're going to be looking
at pharmaceutical product development. in vitro,
in vivo correlation. And we're going to explore
why those failures happen. But maybe even more
important than that, what we can learn from them.
It's like, you know, you learn more from your
mistakes than your successes, right? Absolutely.
That's a great way to put it. And especially
in the world of pharmaceuticals, you know, it's
high stakes. Developing a new drug can take like
over a decade and it can cost literally billions
of dollars. Billions. Well, so understanding
those failures, those those missteps along the
way is super crucial to making the whole process
smarter, faster and getting safe and effective
treatments to patients. Right. OK, so let's let's
unpack this. What are some of the most common
reasons why drug candidates fail? OK, well, you
have, well, the most obvious one, and that's
safety. You know, a drug might just sail through
early testing, everything looks good, but then
later you find unexpected side effects that are
just, well, too risky for patients. Right, right,
of course. You wouldn't want to release a drug
that's going to cause more harm than good, no
matter how promising it seems at first. So what
else can kind of trip these drug candidates up?
OK, so another big one is efficacy. You know,
a drug can look amazing, really great on paper
in early trials, but then when you get to larger
groups of people, it just doesn't, well, it doesn't
deliver the therapeutic punch that researchers
were hoping for. So it's like a movie trailer
that promises an action packed blockbuster, but
then the actual film is a total dud. Exactly.
You got it. And then you have technical challenges,
which can be really frustrating. You know, you
might have problems scaling up the manufacturing
process or the drugs formulation. You know, how
the drug is delivered might not be right. It's
kind of like having all the right ingredients
to make a delicious cake, but your recipe is
not quite right. So you end up with a soggy mess.
Yuck. OK, so how does this book that we're looking
at today, with its focus on in vitro and in vivo
correlation, how does that help researchers navigate
all of these potential problems? Well, one of
the key takeaways is that it's really important
to understand how a drug behaves in a controlled
lab setting, so in vitro, and then how it performs
in a living organism, in vivo. By bridging that
gap, you can really get a better handle on those
safety, efficacy, and technical issues early
on in the development process. Oh, OK. I see.
So it's kind of like a dress for her. before
a play opens. You can work out all the kinks
before the real show. That's a great way to think
about it. And something else that's really important,
and the book dives into this, is formulation.
You know, it's not just about getting the drug
into the body. It's about getting it to the right
place in the right amount at the right time.
Think of it like a delivery service. It needs
to get a package to the right address, undamaged
and on time. Okay, that's a good analogy. So
how a drug is formulated, you know, is it a pill?
an injection, a patch, a nasal spray, that can
really make a difference in how well it works.
Absolutely. It makes a huge difference. And this
is super important for drugs that are meant for
long -term treatment, where you really need reliable,
consistent delivery. Because if the formulation
is off, you run into a lot of problems. Reduced
effectiveness, or maybe even worse side effects.
Oh, wow. So you're saying that either the drug
has the potential to be a total game changer.
If the delivery system is poorly designed, it
can just completely tank its chances of success.
That's exactly right. And that's why so much
time and effort goes into fine -tuning formulations
and testing them rigorously, both in vitro and
in vivo. Wow. OK. It sounds like... It sounds
like they're trying to crack a complex code,
trying to find that perfect combination of ingredients
and delivery methods to really unlock a drug's
full potential. But how do they even start to
predict if a drug has a chance, like a fighting
chance, of making it through this whole process?
Well, there's a bunch of different tools and
models they use. And this book focuses on one
that's really interesting. It's called The Maximum
Absorbable Dose, or the MAD number. The MAD number,
what's that? OK, so it's this calculation that
takes into account the drug's solubility, how
well it dissolves in your stomach, and intestines,
how fast it gets absorbed into the bloodstream
and how long it stays in your system. So it's
kind of like a fuel gauge for medication. Yeah.
Like telling you how much of the drug your body
can take in and use. Exactly. You got it. And
what's really fascinating is that even some common
medications have surprisingly low MAD numbers,
which might explain why they're not as effective
as we might hope. So are you saying that Like
even if you take a higher dose of a medicine,
your body might not be able to absorb and use
all of that extra. That's exactly what the MAD
number suggests. It shows how important it is
to really understand a drug's absorption because
just like upping the dose isn't always the solution.
This is making me rethink like everything I thought
I knew about medicine. So if this MAD number
is so important, how do they like measure it?
Do they have some super high tech equipment that
can like track each molecule of a drug through
the body? Well, it's not quite that simple, but
they do use a mix of lab techniques and math
models to estimate the MAD number. They look
at how the drug dissolves in different solutions,
how it interacts with cells and tissues, how
it's metabolized and eliminated from the body.
So it's kind of like detective work, like you're
piecing together clues from different places
to try and see the bigger picture of how a drug
behaves. Exactly. That's a great way to put it.
And as they, you know, as they gather more data,
their models get more refined and they get a
clear picture of the drug's potential and its
limitations. So it sounds like those early failures,
the ones that don't make the headlines, those
can actually provide a lot of really valuable
insights for future strategies and lead to more
successful outcomes. Definitely. Each failure,
it's a chance to learn to adapt and improve the
whole process. It's about turning setbacks into,
you know, like stepping stones to get to better
treatments. Wow, that's amazing. So we're really
getting a behind the scenes look at the incredible
amount of research and effort that goes into
just developing the medicines that we take every
day. That's right. It's a constant process of
discovery and refinement. And those failures,
they're not the end. They're part of the journey
toward better health. That's really cool. OK,
so we've talked a lot about about solubility,
and it sounds like that plays a key role in how
a drug is absorbed. But what about permeability?
How does that fit into all this? Yeah, so permeability
is the other half of the puzzle when it comes
to absorption. So permeability refers to how
easily a drug can pass through the walls of your
intestines and into your bloodstream. OK, so
if solubility is like getting a key to unlock
the door, permeability is making sure that the
door is actually wide enough to walk through.
You got it. That's a great way to put it. And
just like a door can be too narrow, certain drugs
have trouble crossing those barriers, even if
they dissolve well in your digestive system.
Huh. This reminds me of those escape rooms, where
you have to solve all these puzzles to unlock
the exit. Oh, yeah. It seems like drug absorption
is its own kind of escape room. With solubility
and permeability, as the keys to get out. Yeah,
I like that analogy. And just like in an escape
room, teamwork and strategy are key. Researchers
need to think about both solubility and permeability
when they're designing medications. So are you
saying that some drugs might be, like, super
soluble, but struggle to get through those intestinal
walls, while others might be really good at permeating,
but then they have a hard time dissolving in
the first place? Exactly. And that's where the
biopharmaceutical classification system comes
in. Or BCS, for short. The BCS. Okay, now that
sounds interesting. Tell me more. OK, so the
BCS, it's a system that puts drugs into categories
based on their solubility and permeability. And
it helps researchers make the drug approval process,
well, a little bit smoother. And it helps them
find potential challenges early on. OK, I am
definitely hooked. Let's unpack this BCS and
see how it helps researchers navigate this whole
world of drug absorption. All right, let's do
it. So the biopharmaceutics classification system,
the BCS. Ready to dive in? Yeah, let's do it.
It sounds like this BCS is like a sorting hat
for drugs, like in Harry Potter. Oh, yeah. It
puts them in different categories based on their
magical properties, or in this case, their solubility
and permeability. So how does it work, this sorting
hat? OK, so imagine a grid, OK? Solubility is
on one axis, and permeability is on the other.
The BCS takes drugs and divides them into four
classes, depending on where they land on this
grid. OK, OK, I'm picturing it. So what are the
classes? All right, so you have class one drugs.
Those are like the stars of the show, you know.
They have high solubility and high permeability.
They dissolve really easily in your gut. No problem
getting through those intestinal walls and right
into the bloodstream. They're like the overachievers.
Oh, so they're like the VIPs. They get the red
carpet treatment all the way into the bloodstream.
Exactly. And from a formulation standpoint, they're
easy to work with. Now, class two is a little
different. They have low solubility, but high
permeability, so they can get through those barriers,
but it's harder to get them to dissolve properly.
So it's like having a really powerful engine,
but a really, really clunky transmission. Yeah,
that's a good way to put it. You gotta figure
out how to harness all that power. Exactly. So
that's where those clever formulation strategies
come in. Researchers might, like, make the drug
particle smaller or add, like, Special ingredients
excipients. I think they're called to make it
dissolve better and get absorbed better, huh?
This is making me realize how much goes into
just designing a simple pill, you know, it's
really complex Okay, so what about class three?
You said those were the high solubility low permeability
drugs What what are they like? Those are the
ones that dissolve really well but then they
like hit a wall literally when they try to cross
over into the bloodstream. Like you've got a
smooth on ramp to the highway but then there's
a huge traffic jam. Frustrating. So how do researchers
like get around that? Well, that's where things
can get a little bit tricky. They might try,
you know, different delivery methods like injections
or those patches that you stick on your skin
to kind of bypass the gut altogether. Or, you
know, maybe they try to find a way to make the
drug better at like sneaking through those cell
membranes, you know, like by adding something
to the formulation to like boost its penetrating
power. So it's all about finding workarounds
to those delivery challenges. OK, so we have
one class left. What about those low solubility,
low permeability drugs? Class four, right? Yeah,
class four. And yeah, those are, well, they're
the toughest ones. They're the real problem children.
They have trouble dissolving A and D being absorbed.
It's like, you know, trying to drive a beat up
old car up a mountain during a blizzard. Oh,
yikes. Not a good situation. No. So yeah, finding
a good formulation for those drugs, that can
be a real uphill battle. So are class four drugs
like... a lost cause, do any of them ever make
it to market? It's way harder for sure, but it's
not impossible. There are all kinds of really
smart people out there working on new technologies,
nanoparticles, liposomes, even things like gene
therapy to try and get over those solubility
and permeability hurdles. Wow, it's incredible,
all the work that goes into this stuff. You mentioned
before that the BCS streamlines the drug approval
process, right? How does it do that? Yeah, so
for those class one drugs, the ones that are
really well behaved, the approval process is
usually, well, it's a bit easier. They're absorbed
so well that you can get away with simpler studies
to show that they're safe and that they work.
OK, that makes sense. So less hassle for researchers,
and hopefully patients get access to new treatments
more quickly. Right. But what about the other
classes? Do they get stuck in regulatory limbo?
Not necessarily, no. The BCS, it really helps
researchers kind of see potential problems coming
and adapt their strategies. Like, if they know
a drug is class II with that low solubility but
high permeability, they can really focus on tweaking
the formulation to make the dissolving part better.
So it's like having a roadmap for drug development.
It shows where the bumps in the road might be
and helps them find the best route. Yeah. That's
a great way to think about it. And all of this,
like, helps patients in the end. Great. Right?
Because it makes sure that those pills or injections
are, well, they're formulated and delivered in
the safest and most effective way possible. Exactly.
The BCS isn't just, like, some abstract scientific
thing, you know? It has real -world consequences
for the medicines we depend on. This is really
giving me a new perspective on the whole pharmaceutical
industry. But... even with this BCS system and
that MAD number we talked about, it feels like
there's still a lot we don't know about how drugs
work in the body, right? Oh, for sure. These
are just tools, right? They're a starting point.
But the real key is combining those insights
with a deep understanding of how drugs are absorbed
and distributed and metabolized and all of those
dynamic processes. So it's not just about crunching
numbers and looking at data. It's understanding
the dance between chemistry and biology. Like
how they work together to determine how a drug
behaves. Yeah Are you saying that those those
early failures in drug development those actually
help us understand that better? Exactly. You're
absolutely right those failures the setbacks
they force researchers to go back and refine
their models and and Question what they thought
they knew and in the end that helps them get
a better understanding of how to make really
effective medications It's all about learning
from your mistakes and pushing those scientific
boundaries. It's like Those failures, they're
whispering secrets, showing us like hidden paths
and unexpected problems that we need to solve
to make better treatments. Okay, I think I'm
starting to see the big picture here. Drug development,
it's this intricate dance between like scientific
knowledge, creative problem solving, and being
okay with failing, you know, because that's how
we learn. That's a perfect way to put it. And
it's all driven by, you know, that one big goal
to improve people's health and wellbeing. This
deep dive has been incredible, but before we
wrap things up, I have one more question that's
been kind of bugging me. We've been talking about
how a drug gets into the bloodstream, but what
happens after that? How does it get to where
it needs to go in the body? What are the things
that can affect that journey? That's a great
question, and that takes us to the world of pharmacokinetics.
That's all about how drugs move through the body.
But before we go there, maybe we should take
a minute to, you know, think about what we've
learned so far. Let everything sink in a little.
OK, yeah, a little mental break sounds good.
We'll be right back to explore the next stage
of the drugs adventure. All right, so we're back
and ready to keep going with our deep dive into
drug development. You know, you've walked us
through this whole maze of solubility and permeability
in the BCS, and now I really want to know what
happens after a drug actually makes it past that
absorption obstacle course. Right, so that's
where pharmacokinetics comes in. Basically, it's
the study of how drugs move throughout the body,
how they're absorbed, how they're distributed,
metabolized, and eventually eliminated, kind
of like... like tracking a package from the warehouse
to its final destination. OK. So if we go back
to that delivery service idea that we were using
before, it's like we've just gotten the package
delivered to the front door, but now we have
to follow it inside and see how it gets to the
right room. Exactly. And just like a package
can run into detours or roadblocks along the
way, a drug might have trouble getting to where
it needs to go in the body. It might run into
some enzymes in the liver that want to break
it down or Or maybe it'll bind to proteins in
the blood, which makes it harder to move around.
Wow. So even when a drug gets into the bloodstream,
it's still not like home free, right? It's like
going through all these checkpoints, all these
biological security measures. That's a great
way to put it. Yeah. Yeah. And that's why understanding
for making drugs that actually work. Researchers
have to think about not just how well the drug
gets absorbed, but also what it does once it's
in the body, how it interacts with different
organs, and how it finally gets eliminated. So
it's like designing a delivery system that can
get that package to the right house, to the right
room, make sure it gets opened at the right time,
and used correctly. Exactly. A perfect analogy.
And that's really why drug development is so
complex. It's not just about. chemistry and biology,
it's also physiology, even physics. It's about
solving all these puzzles, being prepared for
problems, and figuring out how to get the right
amount of the drug to the right place at the
right time. So what you're saying is the success
of a drug doesn't just depend on those inherent
properties, like the solubility and permeability
stuff we talked about, but it also depends on
how it how it moves through this whole network
of biological pathways and processes. You got
it. It's a real balancing act. And that's, you
know, one of the big reasons why drug development
is so hard and why so many drugs that look promising
just, you know, they fail at some point. This
has been so fascinating. I never realized how
much goes into creating the medicines that we
take every day. You know, it really is incredible.
You know, it's testament to human ingenuity and
how much we want to, you know. to improve our
health. And even though most drugs never even
make it to market, every single failure teaches
us something. Every setback, it helps to pave
the way for new discoveries, for breakthroughs.
Okay, there you have it folks. We've gone on
this whirlwind tour of the world of drug development
from those early stages in the lab all the way
to that moment when you take a pill or get an
injection. We talked about solubility, permeability,
the BCS, the challenges of creating the right
formulation and getting the drug to the right
place, and of course the importance of understanding
pharmacokinetics to see how the drug actually
works in your body. Absolutely, and I hope after
this deep dive that you have a new appreciation
for how complex it is to bring new medicines
to the world. Those tiny pills that we take,
they represent years and years of research, countless
experiments, and the commitment of so many scientists
and researchers. And remember, there's always
so much more to learn. So, you know, keep those
questions coming. We'll be back with another
deep dive into the world of science soon.