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Figure 6.5
Compartmental absorption of GLK
Several other examples from the literature summarize values of the
input parameters employed to design GI absorption models for the
selected drugs. One of the most detailed descriptions of modeling and
simulation strategy using GastroPlus™ was given by Zhang et al. (2011),
who used carbamazepine (CBZ), a BCS class II compound, as an example
to illustrate the general steps of applying mechanistic modeling and
simulation to identify important factors in formulation design and discuss
important aspects of modeling and simulation. Four oral dosage forms of
CBZ, namely IR suspension, IR tablet, extended-release (XR) tablet, and
XR capsule, under both fasted and fed state were modeled. The required
input parameters were collected from the literature, New Drug
Applications (NDAs), Abbreviated NDAs (ANDAs), or
in silico
predicted,
except the particle density for the IR tablet, which was a GastroPlus™
optimized value. A summary of the CBZ input parameters employed for
ACAT model simulation is presented in Table 6.6.
The PK parameters and ASFs were obtained by two methods. The fi rst
method included deconvolution of the PK data for IR suspension under
fasted conditions, to obtain systemic CL, V
c
, distribution constants
between central and peripheral compartments (K
12
, K
21
), and absorption
rate constant (K
a
), and t
lag
. These values were then fi xed and the ASF
values were optimized to obtain the physiology model. The optimized
ASFs were about 10 times higher than the default Opt logD Model
values, indicating rapid absorption of CBZ in the small intestine. The
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