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Comparison of PK parameters between Model 1 and
Model 2 predicted and
in vivo
observed data
Table 6.3
Parameter
Model 1
Model 2
Observed Simulated % PE*
Simulated
% PE*
C
max
(μg/mL)
3.19
3.21
−0.63
3.39
−6.16
t
max
(h)
4.00
3.15
21.25
3.40
15.00
AUC
0
→
t
(μg h/mL)
25.78
25.96
−0.70
25.69
0.35
AUC
0
→
∞
(μg h/mL)
30.96
29.10
6.01
27.92
9.82
* % PE - percent prediction error
According to the obtained data, both Models 1 and 2 gave accurate
predictions of nimesulide average plasma profi le after oral administration.
In both cases, the percentage prediction errors for C
max
and area under
the curve (AUC) values were less than 10%, indicating that the models
have predicted these parameters well. The largest deviation was observed
for t
max
(PE of 21.25a/a and 15% in Model 1 and Model 2, respectively).
Nevertheless, the predicted values of 3.15 h (Model 1) and 3.4 h (Model
2) were considered as reasonable estimates, since the reported t
max
values
after oral administration of nimesulide IR tablets varied between 1 and
4 h (Jovanovic et al., 2005; Rainsford, 2006).
However, according to Model 1, the resultant ASF values in the
duodenum and jejunum were much higher than the default GastroPlus™
values, refl ecting fast absorption of NIM in the proximal parts of the
intestine. There were two distinct interpretations: Model 1 outcomes
indicated involvement of infl ux transporters in nimesulide absorption,
while according to the Model 2 outcomes, the pH-surfactant induced
increase in drug solubility was a predominant factor leading to relatively
rapid absorption in the proximal intestine. It should be noted that the
Model 2 assumption was supported by the concept of Biopharmaceutics
Drug Disposition Classifi cation System (BDCCS), according to which
BCS class II drugs are not expected to be substrates for infl ux transporters
(Wu and Benet, 2005). In addition, parameters for which accurate data
were not available (i.e.
in vivo
solubility and human jejunal permeability)
were optimized in Model 2. Also, Model 2 was developed using the set of
in vivo
data for two dosage forms (oral suspension and IR tablet), and
revealed incomplete drug absorption from the IR tablet (∼70% of the
administered dose, as compared to almost 100% drug absorbed estimated
for the same set of
in vivo
data when Model 1 was applied). This fi nding
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