33 - Safety Pharmacology & Off-Target Screening (S3E3)

Welcome back to the Deep Dive. Today we're gonna
be looking at early safety testing in drug development.
Specifically, safety pharmacology and off -target
screening. Sounds pretty intense. It is, actually.
Yeah. Because it's all about making sure new
drugs are safe before they even get near human
trials. Right, catching those problems early
is key. So say you're a scientist, you've got
this amazing new drug you're working on. Where
do you even start with safety? What's the first
thing you check? Well, one of the most fundamental
things is, like, how does this drug interact
with the body? How is it absorbed, distributed,
metabolized, and excreted? Like, the whole process.
We call it ADME. ADME. Got it. So why is that
so important for safety? I mean, it's just, like...
where the drug goes, right? Right. But understanding
ADME helps us predict, you know, predict how
a drug will behave in the body. Like if a drug
gets absorbed too fast, you might get like a
sudden spike in concentration and boom, you've
got an adverse reaction. Or if it doesn't break
down properly, it can build up and become toxic.
Makes sense. Like it's a delicate dance between
the drug and the body. Got to understand the
steps to make sure things go smoothly. Exactly.
And one of the one of the key things we look
at is the apparent volume of distribution. We
call it V. It tells us how much the drug spreads
throughout the body. OK, V for volume. But how
do you measure a volume when it's like not a
real physical space? You know what I mean? Yeah,
it's a theoretical concept, but it's based on
real measurements. So we look at the drug concentration
in the plasma after we give a known dose. If
that concentration is low, it means the drug
spread out a lot, leading to a large V. OK. Think
of it like this. Imagine pouring like a cup of
colored water into a bathtub. If the color stays
concentrated, the volume's small. But if it spreads
out through the whole tub, that's a large volume.
Ah, that's a great analogy. So a drug with a
large V would be like that color going everywhere.
It really gets around. It does. That'd make it
riskier, though. I mean, spreading out like that.
It can. A large V often means the drug is reaching
more tissues and that increases the chance of
what we call off -target effects. Off -target
effects. You mean like the drug hitting things
it's not supposed to. Exactly. And those off
-target effects, well, they can lead to some
pretty unexpected and sometimes even harmful
side effects. Oh, wow. So how do you try to catch
those off -target effects early on? Well, we've
got a few tools we use. One of them is the HERG
assay. It focuses on potential heart risks. It
refers to a specific gene that codes for a potassium
channel in the heart. It's super important for
regulating the heart's rhythm. Oh yeah, those
potassium channels. They help control the electrical
activity of cells, right? Exactly. And if a drug
blocks that H -E -R -G channel, it can mess up
those electrical signals in the heart. And that
could lead to some really dangerous arrhythmias.
So the H -E -R -G assay is like a heart safety
check. Are there other early safety tests like
that? Yeah, another one is the liver enzyme assay.
It helps us identify drugs that might be toxic
to the liver. Right, the liver's... like the
body's big detox center. It breaks down all kinds
of stuff, including medications. Exactly. The
liver has all these enzymes that break down drugs,
and if a drug messes with those enzymes or directly
harms liver cells, well, you can get liver damage.
So, HERG is for heart risks, and the liver enzyme
assay is for liver risks. What about all the
other potential off -target effects, like...
Everything else in the body. Well, that's where
things get that's where things get more complicated
There are so many potential targets in the body.
It's impossible to test for all of them Yeah,
that makes sense. So how do you even start to
figure that out? What are the next steps in this
whole safety investigation? Well, that's where
off -target screening comes in. It's kind of
like detective work. We try to find those hidden
clues about how a drug might be interacting with
stuff it shouldn't. So instead of just looking
for heart or liver problems, you're kind of casting
a wider net, seeing if the drug is causing trouble
in other places. Exactly. One way we do that
is with computational modeling. We use computer
programs to predict those off -target interactions
based on the drug structure. So you're looking
for patterns and similarities between the drug
and known targets in the body. Right. Trying
to spot those red flags where the drug might
bind to something it's not supposed to just based
on its shape and what it's made of. It's like
trying to figure out if a key will fit in a lock
just by looking at it, even if you've never seen
the lock before. That's a great analogy. Yeah.
But we don't stop there. We also use experimental
techniques, like high throughput screening. High
throughput screening? That sounds pretty intense.
It is. We basically test the drug against a huge
library of potential targets, proteins, enzymes,
receptors, to see if it binds to anything we
weren't expecting. So it's like a massive fishing
expedition. But instead of fish, you're looking
for off -target interactions. Yeah, but a very
targeted and sophisticated one. This process
gives us a ton of data that we have to, you know,
carefully analyze to see if there are any potential
problems. I can imagine. But even with all this
fancy technology, it seems like predicting every
possible off -target effect would be, well, pretty
much impossible. You're right. The human body
is incredibly complex, and there's always a chance
of unexpected interactions. That's why it's so
important to keep monitoring things even after
a drug is approved and people are taking it.
So the safety investigation doesn't end when
the drugs like available at the pharmacy? Nope,
not at all. Post -marketing surveillance means
we keep an eye on the drug's safety once it's
out in the real world. Doctors and pharmacists
are really important for this because they report
any bad reactions they see in their patients.
So it becomes like a big team effort to track
how the drug's behaving in a much larger group
of people. Exactly. And if we start seeing an
unexpected side effect, we can investigate more
to see if it's caused by an off -target interaction.
We might look at where the drug is going in the
body and how much of it there is to see if it's
building up in a certain organ. Or we might look
at how it's being broken down to see if it's
messing with the body's natural ways of getting
rid of toxins. It's like putting together a puzzle.
using all the information we have about the drug
and how it interacts with the body to understand
why a certain side effect might be happening.
That's a great way to put it. And the more pieces
we have, the clearer the picture gets. But even
with all this monitoring and investigation, there's
always, like, a bit of uncertainty in drug development.
We can try to minimize risks, but we can't get
rid of them entirely. So it's a balancing act,
right? Yeah. Weighing the potential benefits
of a new drug against the potential risks. But
who gets to decide where that balance lies? Who
makes the rules for safety testing? That's where
regulatory agencies come in. Organizations like
the FDA here in the U .S. and the ICH, the International
Council for Harmonization, they set those strict
guidelines for drug safety testing. So these
agencies are kind of like the guardians of drug
safety, making sure that new medications are
really thoroughly checked out before they get
to patients. Exactly. They look at all that data
from the preclinical studies we talked about,
the HERG assay, the liver enzyme assay, the off
-target screening, and they also oversee the
clinical trials where the drug is actually tested
in people. Clinical trials. That's where things
go from the lab to real people. How do those
work? Well, usually there are three main phases
of clinical trials before a drug can be approved.
Three phases. So what happens in each one? Well,
phase one is the first time we really get to
see how the drug works in people. We test it
in a small group of healthy volunteers just to
see how well it's tolerated and how it's absorbed
and eliminated and what kind of side effects
it might have. So it's like putting those ADME
properties we were talking about earlier to the
test in real life. Exactly. We're getting that
real human data. Yeah. And then we move to phase
two, and that's where we actually start testing
the drug in a larger group of people who actually
have the condition the drug is supposed to treat.
Oh, OK. Oh, it's not just about safety anymore.
It's also about whether the drug actually works.
Yeah, exactly. We call that efficacy. Like, does
it actually do what it's supposed to do? But
of course, we're still watching out for safety
and side effects, too. And finally, we have phase
three, which is, well, it's the biggest and the
most expensive phase. This is where the crowds
come in, right? That's right. The drug is tested
in thousands of patients, sometimes even across
multiple countries, just to be really sure about
its efficacy and safety in all sorts of different
people. It's all about getting solid data before
we can even think about submitting it for approval.
Wow, it's a long road. From those first safety
tests to these huge clinical trials, it sounds
like every step is designed with safety in mind.
It really is. And even then, even after a drug
is approved and people are taking it, remember
we still keep monitoring for any problems through
post -marketing surveillance. It's like a lifelong
commitment to making sure these medications are
safe. It makes you realize how much work goes
into bringing a new drug to market and all the
different things that have to be considered.
It is a complex process, but it's all driven
by this need to keep patients safe. We want to
make sure that the medications people depend
on are as safe and effective as they can be.
Well, I think we definitely dug into some of
that complexity today. It's been a really eye
-opening deep dive. I'm leaving here with a much
better understanding of how drug safety testing
works. the dedication of all the scientists who
work so hard to protect us. I'm glad to hear
that. It is a fascinating field and honestly
it deserves more attention. For sure. So to all
our listeners out there, I hope this deep dive
give you a better understanding of the whole
process. You know, all those steps that go into
ensuring the safety of the medicines we all rely
on. And remember, the next time you see a new
drug at the pharmacy, think about that whole
journey it took to get there, all that careful
scrutiny it went through. Thanks for listening
to the Deep Dive. We'll catch you next time.