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Summary of nimesulide input parameters employed
for GI simulation ( continued)
Table 6.1
Parameter
Model 1
Model 2
Blood/plasma conc. ratio
0.668 c
1 g
Unbound percent in plasma (%)
4.513 c
3 a
CL (L/h/kg)
0.039 h
0.028 a
Vc (L/kg)
0.226 h
0.14 a
Elimination half-life ta/a (h)
4.02
3.42
Simulation time (h)
15
Dosage form
IR tablet
IR suspension/
IR tablet
a literature values taken from Rainsford, 2005; b literature values taken from Dellis et al.,
2007; c in silico predicted (ADMETPredictor™ module); d optimized values; e literature
values taken from Jovanovic et al., 2005; f experimental value (Grbic et al., 2009);
g default GastroPlus™ values; h literature values taken from Bernareggi, 1998.
Model 1 was constructed, assuming that nimesulide might be a
substrate for infl ux transporters in the intestine. Therefore, the ASFs
were adjusted to best match the resultant profi le to the in vivo observed
data (Table 6.2). Experimentally determined intrinsic solubility was used
as the input value, and human jejunal permeability was in silico predicted.
Drug particle radius was assumed to be 5 microns. All other parameters
were fi xed at default values that represent human fasted physiology.
The approach used to construct and validate Model 2 was based on the
comparative study of two dosage forms of nimesulide (immediate-release
(IR) suspension and IR tablet). The absorption model was initially
constructed for IR suspension, and was afterwards validated for IR tablet
formulation. The main premise in Model 2 was that nimesulide is well
absorbed after oral administration mainly due to the pH-surfactant
induced increase in solubility in the GI milieu. Therefore, the ASFs were
kept on default GastroPlus™ values (Table 6.2), and input solubility and
permeability values were optimized to best match the in vivo data.
The simulation results were compared with actual clinical data
(Jovanovic et al., 2005), in order to identify the model yielding the best
estimation.
The simulation results (nimesulide plasma concentration-time profi les,
absorption and dissolution profi les, and the predicted and in vivo
observed PK parameters) obtained using the Model 1 and 2 input data
sets, are presented in Figure 6.3 and Table 6.3.
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