CPT Pharmacometrics & Systems Pharmacology,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 22, 2024
Abstract
Time‐dependent
pharmacokinetics
(TDPK)
is
a
frequent
confounding
factor
that
misleads
exposure‐response
(ER)
analysis
of
therapeutic
antibodies,
where
decline
in
clearance
results
increased
drug
exposure
over
time
patients
who
respond
to
therapy,
causing
false‐positive
ER
finding.
The
object
our
simulation
study
was
explore
the
influence
clinical
trial
designs
on
frequency
findings.
Two
previously
published
population
PK
models
representative
slow‐
(pembrolizumab)
and
fast‐onset
(rituximab)
TDPK
were
used
simulate
virtual
patient
cohorts
with
time‐dependent
impact
varying
number
dose
groups,
range,
sample
size
evaluated
time.
Study
single
tested
level
showed
high
probability
showing
When
has
slow
onset,
use
measures
from
early
timepoints
significantly
reduces
risk
false‐positive,
while
fast
onset
it
did
not.
Randomization
two
levels
greatly
reduced
risk,
threefold
or
greater
range
offering
greatest
benefit.
likelihood
increases
larger
size,
care
should
be
taken
identify
factors.
Clinical
supports
appropriate
design
adequate
exploration
can
reduce
but
cannot
entirely
eliminate
misleading
Journal of Translational Medicine,
Journal Year:
2024,
Volume and Issue:
22(1)
Published: Oct. 14, 2024
BI
836880
is
a
humanized
bispecific
nanobody®
that
binds
to
and
blocks
vascular
endothelial
growth
factor
(VEGF)
angiopoietin-2
(Ang-2).
A
comprehensive
biomarker
modeling
approach
presented
here
supported
dose
finding
for
836880.
Advanced Drug Delivery Reviews,
Journal Year:
2024,
Volume and Issue:
unknown, P. 115476 - 115476
Published: Nov. 1, 2024
Model-based
approaches,
including
population
pharmacokinetic-pharmacodynamic
modeling,
have
become
an
essential
component
in
the
clinical
phases
of
oncology
drug
development.
Over
past
two
decades,
models
evolved
to
describe
temporal
dynamics
biomarkers
and
tumor
size,
treatment-related
adverse
events,
their
links
survival.
Integrated
models,
defined
here
as
that
incorporate
at
least
pharmacodynamic/
outcome
variables,
are
applied
answer
development
questions
through
simulations,
e.g.
support
exploration
alternative
dosing
strategies
study
designs
subgroups
patients
or
other
indications.
It
is
expected
these
pharmacometric
approaches
will
be
expanded
regulatory
authorities
place
further
emphasis
on
early
individualized
dosage
optimization
inclusive
patient-focused
strategies.
This
review
provides
overview
integrated
literature,
examples
considerations
need
made
when
applying
advanced
outlook
expansion
model-informed
anticancer
drugs.
CPT Pharmacometrics & Systems Pharmacology,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 22, 2024
Abstract
Time‐dependent
pharmacokinetics
(TDPK)
is
a
frequent
confounding
factor
that
misleads
exposure‐response
(ER)
analysis
of
therapeutic
antibodies,
where
decline
in
clearance
results
increased
drug
exposure
over
time
patients
who
respond
to
therapy,
causing
false‐positive
ER
finding.
The
object
our
simulation
study
was
explore
the
influence
clinical
trial
designs
on
frequency
findings.
Two
previously
published
population
PK
models
representative
slow‐
(pembrolizumab)
and
fast‐onset
(rituximab)
TDPK
were
used
simulate
virtual
patient
cohorts
with
time‐dependent
impact
varying
number
dose
groups,
range,
sample
size
evaluated
time.
Study
single
tested
level
showed
high
probability
showing
When
has
slow
onset,
use
measures
from
early
timepoints
significantly
reduces
risk
false‐positive,
while
fast
onset
it
did
not.
Randomization
two
levels
greatly
reduced
risk,
threefold
or
greater
range
offering
greatest
benefit.
likelihood
increases
larger
size,
care
should
be
taken
identify
factors.
Clinical
supports
appropriate
design
adequate
exploration
can
reduce
but
cannot
entirely
eliminate
misleading
