Population Pharmacokinetic and Exposure–Response Analyses for Ponatinib in the Phase 3 PhALLCON Study
Clinical and Translational Science,
Journal Year:
2025,
Volume and Issue:
18(3)
Published: March 1, 2025
ABSTRACT
In
March
2024,
ponatinib
received
accelerated
FDA
approval
for
the
treatment
of
newly
diagnosed
Philadelphia
chromosome‐positive
acute
lymphoblastic
leukemia
(Ph
+
ALL)
in
combination
with
chemotherapy
based
on
Phase
3
PhALLCON
study
(NCT03589326),
which
demonstrated
a
higher
rate
minimal
residual
disease
(MRD)‐negative
complete
remission
(CR)
at
end
induction
(EOI)
(34.4%)
versus
imatinib
(16.7%;
p
=
0.002).
Patients
(30
mg
QD
reduction
to
15
upon
achievement
MRD‐negative
CR
EOI)
or
(600
QD)
combined
20
cycles
reduced‐intensity
(induction:
cycles;
consolidation:
6
and
maintenance:
11
cycles).
Ponatinib
pharmacokinetics
(PK)
were
similar
patients
previous
population
PK
analysis.
Bayesian
re‐estimation
previously
developed
model
adequately
described
data.
Exposure–efficacy
analyses
did
not
identify
significant
relationship
between
exposure
probability
EOI
(
0.619),
suggesting
consistent
efficacy
benefit
across
exposures.
was
predictor
arterial
occlusive
events,
venous
thromboembolic
thrombocytopenia,
lipase
increase
>
0.05).
However,
exposures
associated
hypertension
0.0340)
alanine
aminotransferase
(ALT)
0.0034).
Dose
from
30
predicted
decrease
odds
experiencing
by
37.7%
ALT
44.2%.
Collectively,
exposure–response
support
favorable
benefit–risk
profile
approved
dosage
reduced
EOI),
chemotherapy,
frontline
Ph
ALL.
Language: Английский
Optimizing Brentuximab Vedotin Dosing in Pediatric Patients with Advanced Hodgkin Lymphoma: A Population Pharmacokinetic and Exposure‐Response Analysis
Clinical Pharmacology & Therapeutics,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 17, 2025
Pediatric
patients
with
advanced‐stage
newly
diagnosed
Hodgkin
lymphoma
(HL)
were
treated
brentuximab
vedotin
(BV)
combined
adriamycin,
vinblastine,
and
dacarbazine
(A
+
AVD).
Weight‐based
BV
dosing
is
employed
in
adult
patients,
while
both
body
weight‐
surface
area
(BSA)‐based
are
used
pediatric
patients.
Data
from
two
studies
for
a
population
pharmacokinetics
(PK)
analysis.
Study
1
was
phase
I/II
dose‐escalation
study
which
relapsed
or
refractory
systemic
anaplastic
large‐cell
HL
received
single‐agent
weight‐based
1.4–1.8
mg/kg
every
3
weeks.
2
tested
BSA‐based
48
mg/m
weeks
AVD
advanced‐stage,
HL.
Sources
of
PK
variability
quantified
using
nonlinear
mixed‐effects
modeling.
The
relationships
between
antibody‐drug
conjugate
(ADC)
payload
monomethyl
auristatin
E
(MMAE)
exposures
progression‐free
survival
(PFS)
incidence
adverse
events
analyzed
by
Cox
proportional
hazards
logistic
regression,
respectively.
Population
models
ADC
MMAE
developed
data
95
BSA
identified
as
significant
covariate
the
clearance
MMAE.
resulted
similar
across
age
groups
(<
12,
12–16,
>
16
years).
A
increase
(
P
<
0.05)
febrile
neutropenia
related
to
increasing
exposure
No
apparent
relationship
PFS.
analyses
support
combination
Language: Английский
A Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective
The Journal of Clinical Pharmacology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: May 2, 2025
Abstract
Targeted
therapies
and
immune
checkpoint
inhibitors
(ICIs)
have
significantly
improved
survival
outcomes
in
metastatic
renal
cell
carcinoma
(mRCC)
but
are
often
associated
with
high
rates
of
adverse
events,
leading
to
dose
reductions
or
treatment
discontinuation.
The
FDA's
recent
initiative,
Project
OPTIMUS,
emphasizes
the
importance
optimizing
dosing
regimens
oncology
clinical
development,
moves
beyond
conventional
maximum
tolerated
approach.
In
this
study,
we
aimed
review
redefine
approved
strategies
for
targeted
ICIs
mRCC
from
OPTIMUS
perspective,
including
pazopanib,
axitinib,
cabozantinib,
sunitinib,
everolimus,
nivolumab.
A
comprehensive
summary
FDA
pharmacology
reviews
studies
performed
routine
practice
was
conducted,
alongside
model‐informed
simulations
pharmacokinetic
profiles
alternative
regimens.
Results
demonstrated
that
actual
doses
were
46.1%
86%
lower
than
dosages,
up
75%
patients
requiring
adjustments.
Model‐informed
suggested
most
therapies,
a
14%–50%
reduction
maintained
comparable
efficacy
while
improving
tolerability.
For
nivolumab,
confirmed
adequate
drug
exposure
flat
regimens,
without
an
increase
effects.
conclusion,
identified
optimized
could
improve
tolerability
maintaining
mRCC.
We
suggest
these
should
be
considered
use
optimal
range
included
labels
support
pharmacokinetically
guided
individualization
practice.
Language: Английский
Integrated modeling of biomarkers, survival and safety in clinical oncology drug development
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.
Language: Английский