31 - Preclinical Toxicology Studies (S3E1)

Welcome back to the Deep Dive. Today we're going
to be talking about pre -clinical toxicology
studies. Yeah. So that super critical step, before
we could even think about giving a new drug to
a person. You sent over a transcript all about
animal toxicology studies. And I think it'd be
great to just kind of unpack that. Yeah. How
do scientists actually use these studies to try
and figure out if a drug is safe before it even
gets near a person? Right. And we can talk about
different study designs, acute, subchronic, and
chronic, all those, and even touch on some of
the rules from the FDA and ICH, you know, the
folks that govern all this. It's a whole world
that most folks just never even think about,
you know? But it's really the foundation for
making sure that drug development is safe. Like,
just imagine. before you or I would ever even
consider taking a new medicine. Scientists have
to be as sure as they possibly can be that it's
not gonna hurt us, you know? That's where these
animal studies come in. Yeah, that makes total
sense. And the transcript you send over, it really
dives into all that, you know? It talks about
acute studies, sub -chronic studies, chronic
studies. What are the big differences between
how those are done? Well, the main differences
are really how long they are and what they're
focused on. Like, think of an acute study kind
of like a quick snapshot, you know? Just a short
-term check to see if there are any immediate
bad effects. Then you've got subchronic studies,
and they're more like, okay, let's take a closer
look over a few weeks, maybe even a few months,
and see what happens when you keep giving the
drug over and over. So acute is like that initial,
is it safe? Yeah, exactly. Okay, we didn't kill
anything, and then subchronic is like, all right,
let's see what happens if we give it for longer.
Exactly. And then you've got the chronic studies,
which can actually go on for years. And those
are really important for figuring out any of
those long -term effects that might not show
up in the shorter studies. Years. Yeah. Years.
Wow. That's a serious commitment to doing this
right. That's wild. So it sounds like we're trying
to get the full picture. The full picture. Of
what could this drug potentially do if somebody
took it for a really long time? We want to know
the good, the bad, and everything in between,
especially when we're talking about medicines
that people might be on for years and years.
Now, I know this is always a tough conversation,
but I think it's important to talk about the
ethics of animal testing. Can you talk a little
bit about what rules are in place to make sure
that these studies are done in the most humane
way possible? Absolutely. So the FDA and the
ICH, they have really, really strict rules in
place. They want to protect the animals and make
sure the data is actually reliable. And one of
the big things they focus on is this idea of
the three Rs, replacement, reduction, and refinement.
Yeah, I've heard of that. But for folks that
maybe aren't familiar with it, could you break
down what each one means? Sure. So replacement
basically means whenever possible, you want to...
try to find another way to do the study that
doesn't involve animals at all, like maybe using
a computer model or doing some tests with cells
in a dish. Reduction means let's use the fewest
number of animals possible while still getting
good data. And then refinement is all about figuring
out how to make the study as painless and stress
-free as possible for the animals. So it's not
just about getting the study done. It's about
getting it done in a way that's as good as it
can be for the animals. Exactly, exactly. It's
about doing the least harm possible while still
getting the information we need to help people.
Gotcha. So we have all these different types
of studies, but what are they actually looking
for? Like, what are some of the specific things
that the researchers are measuring to see if
a drug is safe or not? Well, it really depends
on the specific drug and what it's supposed to
do. But some of the common things we look at
are changes in blood chemistry, how well the
organs are working, and even changes in behavior.
Okay, so it's not just like did the animal die
or not. It's much more nuanced than that. Yeah,
exactly. We're looking for any hint that the
drug might be causing some kind of problem, even
if it's something subtle. So how do they figure
out like how much of the drug to give? I imagine
finding that balance between like giving enough
for it to work, but not so much that it's toxic,
that's gotta be a really tricky thing. It really
is. It's a delicate balance. They usually start
with a really low dose and then slowly increase
it, watching really carefully for any signs of
trouble. The goal is to find that sweet spot,
the therapeutic window where the drug is doing
what it's supposed to without causing too many
side effects. So it's like finding that Goldilocks
zone. Exactly. Where it's not too much. Not too
much, not too little. Not too little, yeah. Right.
I'm sure there have been times where, you know,
a drug seemed really promising in the early stages.
Right. But then later on, some unexpected side
effects popped up, right? Oh, absolutely. That's
why this preclinical testing is so important.
The thalidomide tragedy is a really, really sad
example of why we have to be so careful. Right.
That was the drug they were giving to pregnant
women for morning sickness. Right. And it ended
up causing all those birth defects. Unfortunately,
yes. It was a huge turning point in drug development.
It led to much stricter regulations and a lot
more emphasis on testing drugs in pregnant animals
before they're ever given to people. Yeah. That's
incredibly sad, but also a really important lesson.
It really shows how important it is to make sure
a drug is safe. Absolutely. Even if that means
it takes a bit longer to get it to the people
who need it. Yeah, it's about balancing the need
for new treatments with the responsibility to
keep people safe. Every new drug carries some
risk, and preclinical studies are one of the
best tools we have to try and find and minimize
those risks. It makes you realize just how complex
this whole process is. It is. And how many things
have to be considered before a drug can even
be given to a person. So let's talk a bit more
about the FDA and the ICH. They play a big role
in all this, you know, setting standards and
making sure drugs are safe. Right. What exactly
are they doing when it comes to these preclinical
studies? Well, they basically lay down the law.
They tell researchers what types of studies they
need to do, what kinds of animals to use, what
specific things to measure. It's all very specific.
So they're creating a roadmap, essentially. Yeah,
exactly. That helps make sure the data is high
quality and that everyone's doing things the
same way. Right. They're like the guardians of
public health, making sure that new drugs are
really put through the wringer before they can
be sold. Which is a good thing. You know? Absolutely.
It helps people trust that the medicines they're
taking are safe. Right. And the cool thing is
these regulations aren't just set in stone. They're
constantly being updated as we learn more and
as technology gets better. So it's not just a
like... check the box kind of thing. No, it's
a constantly evolving field. It's all about doing
things better and safer as we learn more. Exactly.
It's amazing to see how all these different pieces
fit together, you know? It is. From the different
types of studies to the ethical considerations
to the role of these big organizations like the
FDA and the ICH. Yeah, it's a complex system.
but it's all ultimately focused on the same goal,
making sure that new medicines are as safe and
effective as possible. That's a great point.
And on that note, let's move on and talk about
volume of distribution, which is a key factor
that tells us how a drug spreads throughout the
body. That's a good one. Yes, let's dive into
that in part two. Okay, so volume of distribution,
right? It's not just about where the drug goes
in the body. It's really about, you know, how
much of it stays in the bloodstream versus how
much of it kind of sneaks off into the tissues.
And that can make a really big difference when
you're trying to figure out the right dose. I
can see how that would matter. Like imagine you
have two drugs that are supposed to treat the
same thing, but they have really different volumes
of distribution. Would that affect how much you
would actually give to a patient? Oh, yeah, absolutely.
Let's say we have drug A, and it just loves to
hang out in the tissue. So it has a large volume
of distribution. And then we have drug B, and
it's more of a home body. It likes to stay in
the bloodstream, small volume of distribution.
So for drug A, if you give a certain dose, you're
not going to see as much of it in the blood because
it's all spread out in the tissue. So to get
the same effect as drug B, you probably need
to give a higher dose. So it's like, if the drug
is hiding out in the tissues, You gotta send
in more to make sure enough of it reaches the
target. Yeah, exactly. That's a good way to put
it. And then on the flip side, with a drug like
drug B that's mostly staying in the blood, even
a small dose can lead to a pretty high concentration
in the bloodstream. So you gotta be careful not
to give too much, you know, to avoid any problems.
So it's almost like personalized medicine, in
a way. You're tailoring the dose based on how
the drug interacts with that specific person's
body? Yeah, you could think of it that way. Now,
how do we actually figure out this volume of
distribution? It's not like we can just, you
know, measure it directly with a ruler or something.
Yeah. Yeah, I imagine it'd be pretty tricky to
track every single molecule of a drug in the
body. Yeah, it's definitely more complicated
than that. What we do is we take blood samples
after we give a known dose of the drug. Let's
say a scientist gives a patient 100 milligrams
of a drug intravenously. Right after they give
it, they take a blood sample and find a concentration
of, say, 10 milligrams per liter. OK, so... We
know how much drug they gave and the concentration
of the blood right afterwards. Then what? So
we can calculate the volume of distribution by
dividing the dose by that initial concentration.
In this case, it would be 100 milligrams divided
by 10 milligrams per liter, which gives us a
volume of distribution of 10 liters. 10 liters.
That seems like a lot. It does. But it's important
to remember that this isn't a real physical volume.
It's more of a theoretical concept that tells
us how much space the drug seems to be distributed
in. That's why we call it the apparent volume
of distribution. OK. It's more about the drug's
behavior, like if it really likes to go into
the tissues, it's going to act like it's spread
out in larger volume, even if that's not literally
true. Exactly. Exactly. It's all about the drug's
preference for certain compartments in the body.
That's pretty wild when you think about it. It
really highlights how important it is to understand
this concept, because it can really help doctors
make better decisions about dosing. Absolutely.
It's one of the key pieces of the puzzle when
we're trying to figure out how a drug is going
to act in the body. Let's move on to another
really important pharmacokinetic parameter, the
elimination half -life. Okay, elimination half
-life. I've definitely heard that term before,
but it'd be great to get a little refresher.
Sure. What exactly does it mean, and why is it
such a big deal in drug development? In the simplest
terms, the elimination half -life tells us how
quickly the body gets rid of a drug. It's the
time it takes for the concentration of the drug
in the blood to drop by half. So for example,
if a drug has a half -life of four hours, after
four hours, 50 % of it is gone from the bloodstream.
Then after another four hours, half of what was
left is eliminated. So now you only have 25 %
of the original concentration. So it keeps halving
over time. Kind of like, I don't know, a radioactive
substance decaying or something. Yeah, that's
a good analogy. So why is this important? Well,
the half -life is a major factor in figuring
out how often you need to give a drug to keep
it working. I can see that. Like, a drug with
a really short half -life would need to be given
more often than a drug with a long half -life.
Exactly. Imagine a drug with a half -life of,
say, one hour. If you just give one dose, it's
basically going to be gone in just a few hours.
So to keep the concentration where you want it,
you'd probably need to give it several times
a day. So frequent dosing is key for those short
half -life drugs. What about drugs with longer
half -lives? Those can often be given less frequently,
maybe just once a day, maybe even once a week,
because they hang around in the body longer,
so you get a more sustained effect. So it's about
finding the right schedule to match the drug's
half -life. You want to make sure the patient
is getting the benefit of the drug without the
concentration getting too low or too high. Exactly.
That's the goal. And this brings us to the idea
of steady state, which is really important for
understanding how a drug works in the body over
time. Okay. Steady state. Tell me more about
that. So when you give a drug over and over again,
its concentration in the body doesn't just keep
going up and up forever. It eventually reaches
a kind of balance point where the amount going
in is equal to the amount going out. And that's
what we call steady state. So it's like a seesaw
that finally finds its balance. Yeah. Perfect
analogy. And guess what? the half -life plays
a big role in how long it takes to reach that
steady state. Usually, it takes about four to
five half -lives. So for our example, drug with
a four -hour half -life, it would take something
like 16 to 20 hours to reach steady state. Yep,
that's right. At that point, the drug's concentration
in the blood would be pretty stable. So I'm seeing
now how understanding both the half -life and
this concept of steady state, it's really crucial
for doctors because it helps them figure out
the best way to give a drug over the long term.
It's like having a roadmap for how a drug is
going to behave in the body. Now, you know, the
transcript you sent mentioned something interesting.
It said that all these pharmacokinetic parameters,
like volume of distribution and half -life, they're
independent of the dose you give, which might
sound a little weird at first. Yeah, I mean,
you would think that giving a higher dose would
lead to a longer half -life, wouldn't you? You
would, but that's actually a common misconception.
Remember, we're talking about drugs that follow
what we call first -order elimination. What that
means is that the rate at which the body gets
rid of the drug is proportional to how much of
the drug is there. So the more drug there is,
the faster the body gets rid of it. Exactly.
If you double the dose, you're doubling the amount
in the body, but you're also doubling how fast
it's being eliminated. Half -life stays the same.
So it's like everyone's running at the same speed
in a race. But some people start further ahead.
That's a great way to think about it. They all
cover the same distance in the same amount of
time. Yep. The elimination half -life is like
a built -in property of the drug. It doesn't
change based on how much you give. Now, there
are some exceptions to this, of course. Some
drugs have what we call non -linear pharmacokinetics,
where the rate of elimination doesn't change
in a straightforward way with the dose. So in
those cases, a higher dose could actually mean
a longer half -life. Right. But those are kind
of special cases. For most drugs, these parameters
are pretty much constant, regardless of the dose.
OK, that's good to know. So for the vast majority
of medications, those parameters are like fixed
points on the map, even if the route we take
might vary. Now what about clearance? How does
that fit into all of this? Ah, clearance. That's
another vital piece of the puzzle. Clearance
is all about how efficiently the body can remove
a drug from the blood. Think of it like the volume
of blood that's completely cleared of the drug
per unit of time. So it's not just how much drug
is eliminated, but how good the body is at getting
rid of it. Precisely. And just like volume of
distribution and half -life, Clearance is an
inherent property of the drug and the body systems
for getting rid of stuff. Things like how the
liver metabolizes the drug, how the kidneys filter
it out, even elimination through the lungs or
sweat. It all factors in. So it's a really holistic
measure that takes into account all the different
ways the body gets rid of a drug. Exactly. And
it's super important for figuring out the right
dose and how often to give it to maintain that
steady state we were talking about. So a drug
with high clearance. meaning the body gets rid
of it really efficiently, would need more frequent
dosing or higher doses to keep the concentration
steady. Exactly. And the opposite is true too.
A drug with low clearance, you wouldn't need
to give it as often, otherwise it could build
up and cause problems. It's all about striking
that balance. Right, it is. Between how much
drug you put in and how quickly the body can
clear it out. Absolutely. Understanding clearance,
along with all the other parameters we've talked
about, it's really essential for making sure
drug therapy is both safe and effective. It's
amazing to me how these concepts, which can seem
kind of abstract at first. I know, right? They
actually have such huge practical implications
in medicine. They really do. It's like this intricate
dance between the drug and the body. So let's
bring it back to preclinical toxicology studies
for a minute. How do these principles actually
play out when we're trying to figure out if a
new drug is safe before we give it to people?
Yeah, that's a great question. I think that's
a perfect segue to part three, where we can really
dive into the details of how these studies are
designed and regulated. All right, let's do it.
OK, so we've laid out some of the basic concepts
of pharmacokinetics and how they kind of tie
into drug development. But now let's circle back
to those preclinical toxicology studies. You
mentioned earlier that they're very heavily regulated,
especially by agencies like the FDA and the ICH.
Can you kind of walk us through that a little
bit? Oh, yeah, absolutely. Preclinical talk studies,
they have to follow a really strict set of rules,
and for good reason. I mean, we want to make
sure that these studies are done ethically, you
know, with the animal's well -being as a top
priority. And also, we need to be absolutely
certain the data we're getting is reliable, data
that we can actually use to figure out if a drug
is safe for people. So it's not just about, you
know, doing the studies. It's about doing them
the right way. Right. Exactly. With a lot of
attention to detail, both from, like, a scientific
point of view, but also from an ethical point
of view. Yeah, you got it. And these regulations,
they lay out all the specifics. What kinds of
studies are needed, what species of animals to
use, what doses to test, how long the study should
run. It's all very clearly defined. So it's like
a standardized approach to make sure that everyone's
doing things in a consistent way and that the
data is reliable, no matter who's doing the research.
That's exactly it. And it's important to remember
that these regulations aren't just, you know,
static. They're constantly being updated as we
learn more, as technology improves and as, you
know, our ethical considerations evolve. Sounds
like it's a pretty dynamic field. Oh, yeah, absolutely.
Always trying to find ways to do things better.
Now, even with these regulations in place, there's
still a lot of room for scientific judgment.
Right. It's not just about checking boxes and
following a script. Right. It takes a lot of
expertise and critical thinking to design these
studies to make sure that they're actually giving
us useful information about how safe a drug is
for people. There are skilled toxicologists involved
every step of the way, you know, from those very
first screens of potential drug candidates all
the way to the final review of the preclinical
data before a drug can even be tested in humans.
It's a good reminder that there are real people
behind all the science, right? Yeah. People who
are dedicated to making sure that these drugs
are as safe as possible. So let's talk about
what researchers are actually looking for in
these studies. What are some of those key endpoints
that help them determine whether a drug is safe
or not? The endpoints we look at in preclinical
talk studies, they can vary a lot. It really
depends on the drug, how it works, what it's
supposed to treat, and any potential risks that
we might have already identified. So it's not
a one -size -fits -all approach. No, definitely
not. Each study is kind of tailor -made for that
specific drug. Exactly, exactly. Some endpoints
are pretty broad, like overall health and survival,
but others are much more specific, like blood
tests to check how well the liver or kidneys
are working. We're basically looking for any
sign that the drug might be causing some kind
of harm, whether it's a general decline in health
or damage to specific organs. So it's not just
about seeing if you know, something really bad
happens. It's also about understanding how the
drug is affecting the body's normal processes.
Exactly. We might look at things like changes
in blood pressure, heart rate, even brain activity,
you know, to see if the drug is having any effects
that we weren't expecting or that we don't want
to see. So it's almost like these studies are
detectives, in a way. Searching for clues about
how the drug is interacting with the body and
trying to identify any potential red flags. I
like that analogy. It really is about gathering
evidence. Evidence that helps us make an informed
decision about whether a drug is safe enough
to move on to human testing. It's pretty amazing
how much work goes into making sure a drug is
safe before it's even given to a human volunteer.
Yeah, it's a huge undertaking. So speaking of
human trials, how do researchers actually figure
out what's a safe starting dose for those first
studies in people? That's a really crucial question,
and the preclinical data is essential for answering
it. Researchers often start with what we call
the No Observed Adverse Effect Level, or NOAEL.
Basically, it's the highest dose that was given
to animals in the studies that didn't seem to
cause any harm. So the NOAEL is like the upper
limit of what we think is safe, based on the
animal studies? Yeah, you could think of it that
way. But when it comes to human trials, we're
even more cautious. We take that NOAEL and divide
it by a safety factor, usually 10 or even 100.
So the starting dose in people is much, much
lower than the highest dose that seems safe in
animals. So it's like we're erring on the side
of caution, big time. Absolutely. We want to
minimize the risk to those brave volunteers who
are the first to try a new drug. And as the trial
goes on, we keep a very close eye on things,
watching for any signs of toxicity, and we only
increase the dose very gradually if it seems
like it's safe to do so. So it's all about taking
things slowly and carefully, putting safety first
every step of the way. Exactly. Now, we talked
earlier about alternatives to animal testing.
What are some of the exciting things happening
in that area? One of the most promising areas
is the development of what we call in vitro models.
These are basically systems that let us mimic
human biology in the lab outside of a living
organism. We're talking about things like really
sophisticated cell cultures, 3D tissue models,
even organ on a chip systems that can simulate
the flow of blood and fluids. So it's like creating
little mini versions of human organs in a dish.
Yeah, that's a good way to think about it. And
the technology is getting better all the time,
right? Oh, yeah. These models are becoming more
and more sophisticated. So researchers can really
start to test how a drug might affect human cells
and tissues. Exactly. It's a really exciting
area. It sounds like we're getting closer to
being able to test drug safety and effectiveness
without having to rely on animal models as much.
I think so, yeah. But it's important to remember
that these in vitro models, they're not perfect
replacements for animal studies just yet. At
least not for all types of research. They still
need to be rigorously validated, and we're still
figuring out the best ways to use them in drug
development. So it's still a work in progress,
but it's definitely a field to watch. Absolutely.
There's so much potential there. Well, this has
been a truly fascinating deep dive. We've covered
so much ground. From the basics of preclinical
tox studies, to the exciting future of things
like in vitro models. I feel like I have a much
better understanding now of all the work that
goes into developing a new drug and all the people
who are dedicated to making sure those drugs
are safe and effective. Well, I'm glad to hear
that. Thank you so much for sharing your expertise
with us. My pleasure. And to our listeners, thank
you for joining us on this deep dive. I hope
you found it informative and maybe even a little
bit inspiring. Until next time, stay curious.