Hello, my name is Mark Rogge, I'm the
Senior Director for Drug Metabolism and
Biogen Idec Corporation.
I've been in industry for about 25 years,
most of my experience is in
the pre-clinical and
clinical development areas.
The topic of my lecture is:
Pharmacokinetics, Toxicokinetics and
We'll start this lecture with
considerations around first-in-human
(FIH) dosing and clinical progression,
discuss expectations for
both the project team and
senior management, talk about terms,
definitions and concepts that
are important around this topic,
follow up with a safety margin example and
finish with some concluding comments.
Let's start our discussion with
first-in-human (FIH) dosing and
clinical progression considerations.
Safety is the most important, in fact,
the paramount consideration as we enter
into and progress through human trials.
The FIH dose is often the most risky dose
in the clinical development program,
since until we have some human data, we
do not understand the pre-clinical safety
database as representative and valid,
in terms of understanding safety issues
that may arise during
the clinical program.
Dose escalation is also
an important consideration.
We must maintain appropriate safety
margins as we progress through, and
approach what we believe is going to
be the maximum dose administered in
the clinical program.
Multiple dose exposure or repeated
administrations in a single patient become
very important, since often in
the pre-clinical setting the regimens
are different from those that will be
administered in the human program.
Consequently, we need to
understand the nature of
Do peak concentrations cause
the toxicity to occur?
Is it maintenance of a concentration above
a threshold that causes the toxicity?
When we begin to understand
we can better relate the pre-clinical
safety database to that database that's
being developed in the human setting.
Often, clinical programs
start in healthy subjects and
then progress into the patient population.
More and more clinical development is
being initiated in the patient population.
Depending on the disease and
the patient population intended to
be treated, it is not uncommon for
these patients to be debilitated, and
therefore a higher safety margin or
lower doses may be warranted as
we initiate that human program.
Special populations are often overlooked.
Special populations encompass children,
the elderly, patients with renal
disease or hepatic disease.
Like patients, they may be more
susceptible to toxicities and
higher safety margins or
lower doses may be warranted.
Let's talk for
a minute about dose selection.
Any therapeutic is going to be
safe if the dose is low enough,
it's also going to be toxic
if the dose is high enough.
It is imperative that the doses we
choose in our human trials are both
intelligent and informative.
Doses must never be so
high that they produce unnecessary risk
of toxicity in the healthy subject or
At the same time, they must not be so
low or infrequently administered that they
do not add value to the clinical database
and allow the program to continue forward.