32 - Pharmacokinetics in Preclinical Testing (S3E2)

Welcome back everybody for another deep dive.
And today we're gonna get into preclinical testing,
specifically pharmacokinetics. Oh, very interesting.
Yeah, so we've got all this research on how scientists
figure out a drug's journey through the body.
And we're talking like way before it even gets
near a human. Yeah, this is like the foundation
of drug development. Absolutely. You know, you
really can't imagine releasing a drug without
understanding how it's. absorbed where it goes
in the body, how it's broken down, and how it
ultimately leaves the system. Got to get out
somehow. Exactly. So that's where this concept
of ADME comes in. Absorption, distribution, metabolism,
and excretion. Got ADME like a roadmap for the
drugs adventure through the body. Yeah. That's
a great way to think about it. But all of this
is happening in animal models, right? Exactly.
Before human trials even start. Yeah. It's all
about getting those early insights. you know,
those data points that are going to tell us how
this drug might behave in humans. There's like
a dress rehearsal with the stand -in for the
human body. That's a good analogy. But how do
they actually study this in animals? These are
like tiny blood draws and urine samples. You're
on the right track. Yeah. Researchers use a variety
of techniques, but blood and urine sampling are
definitely common. OK. That gives them a timeline
of the drug's concentration over time. They also
analyze tissues to see where the drug accumulates.
So it's like a detective tracking the drug's
movements through the body. Exactly. But there's
obviously a lot of variation between, say, a
mouse and a human. All right, of course. So how
do they bridge that gap? Well, that's where this
concept of apparent volume of distribution comes
in. Apparent volume of distribution. About an
actual physical space, but a calculated value.
Okay. It's more like a ratio that helps us understand
how much of the drug is hanging out in the tissues
versus the bloodstream. Okay, so this apparent
volume can even be larger than the actual animal's
body. It can, and that's where it gets a little
bit tricky to wrap your head around. Yeah, how's
that even possible? Think about it like this.
Imagine you add a teaspoon of salt to a glass
of water. OK, it dissolves. Right now, imagine
adding that same teaspoon of salt to a swimming
pool. OK, so the salt is still there, just way
more spread out so the concentration is lower?
Exactly. A large volume of distribution suggests
that the drug is highly dispersed in the body.
It's tucked away in tissues. OK. Whereas a small
volume means it's mostly staying in the bloodstream.
So it's less about literal space and more about
the drug's tendency to explore, so to speak.
Yeah, you could say that. But how do they even
figure out this volume? Well, they run these
experiments. They meticulously collect data.
Right. And then they use some pretty sophisticated
mathematical equations and modeling to calculate
these parameters, these pharmacokinetic parameters.
Sounds incredibly complex, going from these animal
studies to projecting doses for humans. It is.
They have to take into account body weight. potential
drug interactions, even how efficiently the body
breaks down and eliminates the drug, something
we call clearance. Clearance, okay, like the
body's cleaning crew for drugs. Yeah, you could
think of it that way, and all of this is happening
in the preclinical stage, guided by very strict
regulations. Of course, so organizations like
the FDA, the ICH. Right, exactly, they set very
stringent standards. They're watching. They want
to make sure researchers are following best practices,
and ultimately it's all about protecting patients.
It's like a safety net for the entire process.
It is, but it's also important to remember that
these regulations are constantly evolving. Oh,
so this isn't static. Not at all, as science
advances and we learn more about drug development.
The guidelines adapt to reflect the latest knowledge.
That makes sense. So it's a really dynamic field.
Very much so. And it's a critical one because
these early preclinical studies lay the groundwork
for everything that comes after. Absolutely.
And if a drug has like a really large volume
of distribution, wouldn't that make it harder
to eliminate? Wouldn't it linger in the body
longer? That's a great question. And it highlights
how interconnected these concepts are. But before
we jump into that, let's take a closer look at
some specific examples of how researchers actually
calculate these parameters from the animal data.
Let's do it. Yeah, you're absolutely right. A
large volume of distribution can mean a drug
sticks around in the body for a while. So understanding
that value is super important. OK, so back to
my question. How do researchers actually go from
these animal experiments to figuring out the
volume of distribution? Right. Sounds like a
lot of number crunching. It is a lot of number
crunching. They use the data from those blood,
urine, and tissue samples. Right. Let's say they're
studying a new antibiotic. They give a known
dose to the animal. OK. And then they track where
it goes, how fast it's absorbed, all that. Exactly.
They'll take blood samples at different times
and measure how much of the drug is in the plasma.
They might also look at how much ends up in specific
organs. So they're building like a concentration
curve, seeing how the drug levels rise and fall.
That's a great way to picture it. And they use
this data and some pretty fancy math to calculate
that apparent volume of distribution. And that
helps them understand, you know, how much of
that initial dose is actually circulating in
the blood versus how much is sort of hiding out
in the tissues. Got it. So a high concentration
in the tissues would mean a larger volume of
distribution. Exactly. It goes back to that salt
analogy, remember? Yeah, it's swimming cool.
If most of the salt is spread out in the pool
water, the concentration in any given sample
is gonna be pretty low, suggesting a huge volume.
Okay, I'm starting to get it, but why does this
matter so much for drug development? I mean,
it's interesting, but. Well, think about it.
It's all about those dose projections for human
trials, remember? Right. If a drug has a large
volume of distribution, it means it's probably
hanging out in the tissues, maybe even binding
to specific sites. OK, so you might need a higher
dose to get the effect you want. Exactly. You
need enough of the drug to reach those target
tissues and achieve what we call a therapeutic
concentration. Right, enough to actually work.
Exactly. But of course, you have to balance that
with safety. Right. You can't just keep upping
the dose. Exactly. That's where those regulatory
guidelines from the FDA and the ICH are so important.
They want to make sure that the dose is chosen
for human trials, are effective, but also crucially
safe. It's a delicate balance. It really is.
This whole process is so intricate. It's amazing
how much work goes into understanding a drug
before it even gets near a person. It really
is a testament to the complexity of drug development.
Every step from these early ADME studies in animals
to those first human trials is absolutely critical.
Right. And like we said, this is just scratching
the surface of pharmacokinetics. Oh, yeah. We've
only just begun to explore this fascinating world.
Yeah. It really shows how important those early
studies are. It's true. They set the stage for
everything that comes after. Right. And all that
info is what they use to make those decisions
about dosing. for the human trial. Exactly. Researchers
use these complex mathematical models. They factor
in all the data from the animal studies to try
and predict what the optimal dose would be for
humans. It's like a puzzle, using those clues
from the animal data to figure out how to treat
people safely and effectively. It is a puzzle,
and it's not just about making sure the drug
works. It's about minimizing the risks, too.
Right, which is where those guidelines come in.
It's good to know there are safeguards. Absolutely.
The FDA and the ICH play a huge role. They set
these really high standards for pre -clinical
testing to make sure patients are protected.
It's amazing to think that behind every drug
we take, there's this whole world of research
analysis, all these factors to consider. It's
true. And it all starts with that basic understanding
of the drug's journey through the body, those
four letters, ADME. Right, ADME. They represent
like a core concept in drug development. This
deep dive has been so interesting, I feel like
I've got a whole new appreciation for how complex
this is, this whole pre -clinical pharmacokinetics
thing. It's a fascinating area, and it really
shows you how much work goes into developing
the medicines we all rely on. It's like every
drug has a story, and this is just the first
chapter, you know, understanding how it moves
through the body. That's a great way to put it.
Thanks for joining us on this exploration of
preclinical testing. Of course. I hope you've
learned a bit more about how scientists work
to bring safe and effective treatments to everyone.
Absolutely, and a new appreciation for those
animal models that help make it all possible.