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Printable Handouts
Navigable Slide Index
- Introduction
- Lecture outline
- First in human dosing and clinical progression
- A summary of expectations
- Terms, definitions and concepts
- Diazepam absorption and disposition
- Diazepam absorption and disposition (simulated)
- Understanding Cmax and Tmax
- Understanding area under the curve
- Understanding bioavailability
- Understanding bioavailability, Cmax and Tmax
- Understanding distribution volume
- Diazepam distribution volume: human estimate
- The concept of half-life (1)
- The concept of half-life (2)
- The concept of half-life (3)
- Toxicokinetics (1)
- Toxicokinetics (2)
- Evaluations of a major metabolite
- Evaluations of metabolites according to guidance
- Safety margin examples - simple and complex (1)
- Safety margin examples - simple and complex (2)
- Estimating the maximum safe starting dose
- Safety margin and first in human dose
- Steps for selecting starting dose
- Correlation of body surface area and body weight
- Conversion of animal doses to human doses
- Example: FIH dose determination
- Pharmacodynamic and toxicity response curves
- FIH dose estimation based on MRSD guidance
- Concluding comments
- Acknowledgements
Topics Covered
- The pharmacologic and toxic effects of a potential therapeutic agent are a consequence of the product concentration at the site of action
- By understanding inter-species sensitivity to the agent and to the absorption and disposition properties, a rational first in human dose can be determined
- Basic pharmacokinetic elements
- Measures of exposure
- Scaling methods and calculations of relative exposure
- Utilizing outcomes from toxicology evaluations and associated exposure measures
- First in human dose concept
Links
Series:
Categories:
Talk Citation
Rogge, M. (2019, February 26). Pharmacokinetics, toxicokinetics and safety margins [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 7, 2024, from https://doi.org/10.69645/SEPO7206.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Mark Rogge has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Pharmaceutical Sciences
Transcript
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0:00
Hello, my name is Mark Rogge, I'm the
Senior Director for Drug Metabolism and
Pharmacokinetics at
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
Safety Margins.
0:24
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.
0:49
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
the exposure-toxicity-response
relationship.
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
that relationship,
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
patient.
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.