Computer- aided biopharmaceutical characterization: gastrointestinal absorption simulation - Computer-Aided Applications in Pharmaceutical Technology - page 189

indicated that nimesulide dissolution from IR tablets is expected to be the
limiting factor for drug absorption.
Overall, the described independent procedures to build a nimesulide
specifi c absorption model illustrated the importance of understanding
complex interplay between drug physicochemical and PK properties,
formulation factors, and human physiology characteristics, in order to
predict drug PK profi le in vivo . Interpretation of the obtained data
indicated that the approach applied in Model 2 might be considered as
more realistic, signifying that the related absorption model more likely
refl ects nimesulide in vivo absorption. It was also stressed that, in order
to obtain meaningful in silico modeling, the necessary input data have to
be carefully selected and/or experimentally verifi ed.
In the next example, gliclazide (GLK) was used as the model drug to
illustrate general steps of mechanistic modeling and simulation using
GastroPlus™ to predict oral drug absorption. GLK is an ampholyte with
pH-dependent solubility in the GI pH range (Grbic et al., 2011). According
to the BCS, GLK meets the criteria of a low solubility drug. Reports from
the in vivo studies show that, after oral administration, GLK is almost
completely absorbed (Delrat et al., 2002; Najib et al., 2002), although its
absorption rate appears to be slow and variable (Kobayashi et al., 1981;
Hong et al., 1998; Davis et al., 2000). A summary of the input parameters
employed for GI simulation is given in Table 6.4.
In the initial attempt to construct a GLK-specifi c absorption model, Opt
logD Model SA/V 6.1, considering default values for the absorption
gradient coeffi cients C1-C4 (used to calculate the ASFs), was used to
estimate changes in permeability as the drug travels along the GI tract. The
resultant GLK absorption profi le, based on the selected input parameters
(Table 6.4) and default C1-C4 values, diverged from the mean in vivo
observed C p -time data (Najib et al., 2002) (Figure 6.4). Therefore, the
absorption gradient coeffi cients, and consequently, the ASF values, were
adjusted (using the Optimization module) to best match the resultant model
to the in vivo data. Default and adjusted ASF values are given in Table 6.5.
The resultant ASF values in the small intestine, adjusted to best fi t the
observed plasma concentration-time data for GLK IR tablets, were lower
than GastroPlus™ generated values, indicating the possible infl uence of
effl ux transporters on GLK absorption through this part of the intestine.
This assumption was supported by the results of Al-Salami and associates,
who revealed that GLK is a substrate of the ileal effl ux drug transporters
Mrp2 and Mrp3 (Al-Salami et al., 2008, 2009). The generated plasma
concentration-time profi le, based on the selected input parameters along
with the adjusted ASF values, is presented in Figure 6.4.

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