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other approach considered fi tting nine parameters in the ACAT model
(V
c
, CL, K
12
, K
21
, K
a
, mean particle radius, drug particle density, solubility,
and C1 and C2 constants used in calculation of ASFs), using the
Optimization module. Coeffi cients C3 and C4, used to calculate the ASFs
of the colon, were kept as default values. The optimized PK values
revealed no signifi cant differences in comparison to the PK parameters
obtained by the fi rst method; therefore PK parameter values obtained by
fi tting the conventional PK model were used for further simulations.
Stomach transit times of 0.1 and 0.25 h were used for the IR suspension,
and tablet and capsule under the fasted state, respectively, while a
stomach transit time of 1 h was used for all dosage forms under fed
conditions. A colon transit time of 36 h was used for all dosage forms
under both fasted and fed conditions. All other parameters were
GastroPlus™ default values. In the case of XR products, Weibull
controlled-release functions were used as inputs for GI simulation
(Weibull parameters were obtained by deconvoluting mean PK profi les
after p.o. administration of XR tablets and capsules under fasted and fed
conditions).
Predicted CBZ PK profi les were close to the observed mean PK profi les
for all tested CBZ products under both fasted and fed conditions, as
indicated by correlation coeffi cients, which ranged between 0.876 and
0.991. The model was also able to capture the absorption plateau that
exists after oral administration of the investigated CBZ IR tablet under
fasted conditions (the observed peak occupancy time (POT
20
, time span
over which the concentration was within 20% of C
max
) ranged from
3.7 to 41 h under fasted conditions, while the predicted POT
20
ranged
from 2.9 to 40 h).
Regional absorption distribution revealed that CBZ was mainly
absorbed in the small intestine for IR formulation, but in caecum and
colon for XR formulation, under both fasted and fed conditions,
indicating formulation may have signifi cant impact on CBZ regional
absorption (Figure 6.6). Comparing the percentage of drug absorbed in
different GI regions under fasted and fed conditions revealed that food
had the greatest effects on the rate of absorption from the IR suspension
and tablet, and increased CBZ absorption in duodenum.
Another study of CBZ oral absorption simulation using GastroPlus™
was conducted by our group (Kovacevic et al. (2009). The prime objective
of this study was to use GIST, in conjunction with IVIVC, to investigate
a possible extension of biowaiver criteria to CBZ IR tablets. In this
context, GIST was used to predict the fraction of CBZ dose absorbed
under fasted state, and the drug disposition based on its physicochemical
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