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Model Based Neutrophil Guided Dose Adaptation in
Chemotherapy; Evaluation of Predicted Outcome with
Different Type and Amount of Information
Johan E Wallin, Lena E Friberg and Mats O Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
100%
90%
2nd course
Sub
Target
Tox
100%
36%
39%
35%
34%
80%
33%
42%
70%
60%
50%
40%
38%
40%
30%
20%
29%
27%
27%
25% red.
PDlim 1
10%
20%
0%
No adj.
PDlim 1.3
Sub
5th course
Target
Tox
100%
90%
36%
80%
33%
47%
37%
70%
60%
50%
31%
40%
47%
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30%
20%
80%
38%
39%
40%
36%
33%
33%
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33%
33%
40%
40%
39%
41%
31%
27%
27%
28%
27%
45%
70%
60%
31%
50%
35%
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40%
34%
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42%
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10%
c1
PD
fu
ll
PK
ite
...
1
PK
PD
lim
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c
PD
c1
ite
d
..
PD
lim
as
.
c1
+B
c1
+2
PK
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se
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se
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c1
PK
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ed
.2
5%
0%
Fraction of patients experiencing life-threatening toxicity,
target neutropenia or sub-therapeutic/mild toxicity with
different optimization methods
Fraction of patients in target range (Gr 2 or 3
neutropenia) using the limited PD sampling
strategy with varying levels of variability.
90%
36%
ad
j
Methods:
PK and PD data were simulated for one
thousand patients in five treatment courses.
Different portions of data were used to obtain
empirical
Bayes
estimates
that
were
subsequently used to adjust the dose to a level
predicted to result in a target neutrophil nadir.
Performance of the approaches for doseadjustment were evaluated with differentlevels
of IIV and IOV.
27%
N
o
A previously described semi-mechanistic model
for myelosuppression has been used to
characterize a wide range of anticancer
drugs(4), and both interindividual and
interoccasion variability (IIV/IOV) has been
described for a number of agents (5). This
knowledge could be used in a clinical setting to
make model-based dose individualization,
which
compared
to
current
stepwise
procedures, may tailor doses in a more precise
manner, and allow increased overall dose
intensity in the population without increasing the
risk for severe toxicity.
34%
12%
10%
21%
11%
0%
No adj.
Estimation of individual parameters and
adaptation of dose
Sub
Target
Tox
SE
The semi-mechanistic myelosuppression
model
Results:
In the presence of PD measurements, PK data
provided little additional information. By a
limited PD sampling the number of patients on
target could be increased with the model-based
approach compared to standard doseadjustment methods. Thereby the model-based
dose-adjustment
method
could
facilitate
increased overall dose intensity in the
population, without a corresponding increase in
patients experiencing severe neutropenia. The
number of patients achieving target range
neutropenia was increased by 27% compared
to the standard method. Successful dose
adaptation seemed to be more sensitive to IOV
magnitude in the drug efficacy parameter than
in other PK or PD parameters, whereas IIV
magnitude was of little importance.
BA
Introduction:
Chemotherapy-induced neutropenia has been
reported being predictive of patient survival (13). Severe neutropenia is one of the most
important dose limiting events in many
anticancer regimens, and one of the most
employed approaches to this problem has been
to reduce the consecutive dose in fixed steps,
commonly by 25%. Another investigated
approach has been to use pharmacokinetic
Hypothetical utility function given that grade of
(PK) sampling to tailor dosing, but only rarely
chemotherapy-induced neutropenia being
have
model-guided
computer-based
related to probability of survival
approaches
utilizing
PK
and/or
Objectives:
pharmacodynamic (PD) data been used.
In this study we investigated by simulations the
outcome of model-based dose adaptation, and
the influence of type and amount of data
provided to the model. We also investigated the
influence of IIV and IOV magnitudes for
adaptation outcome.
25% red.
PDlim 1
PDlim 1.3
Fraction of patients experiencing life-threatening
toxicity, target neutropenia or sub-therapeutic/mild
toxicity with increasing courses of treatment
Conclusions:
A model-based dose adaptation procedure with
a limited neutrophil measurement schedule may
increase the chance of success in treatment as
it allows for increased dose intensity. When
neutrophil counts are available PK data provide
little additional information on the expected
myelosuppression time-course.
References:
1.
Cameron et al. Moderate neutropenia with adjuvant
CMF confers improved survival in early breast cancer. Br J
Cancer 2003;89(10):1837-1842.
2.
Di Maio et al. Chemotherapy-induced neutropenia and
treatment efficacy in advanced non-small-cell lung cancer: a
pooled analysis of three randomised trials. Lancet Oncol
2005;6(9):669-677.
3.
Poikonen et al. Leucocyte nadir as a marker for
chemotherapy efficacy in node-positive breast cancer treated
with adjuvant CMF. Br J Cancer 1999;80(11):1763-1766.
4.
Friberg et al. Model of chemotherapy-induced
myelosuppression with parameter consistency across drugs.
J Clin Oncol 2002;20(24):4713-4721.
5.
Hansson et al. Comparison of Inter-Occasion and InterIndividual
Variability
in
ChemotherapyInduced
Myelosuppression. PAGE Abstracts of the Annual Meeting of
the Population Approach Group in Europe 2008:Abstract
1328.