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Summary of the GLK input parameters employed for
GI simulation
Table 6.4
Parameter
Value
Molecular weight (g/mol)
323.4
log
P
1.448
a
pK
a
2.9; 5.8; 9.6
b
Human jejunal permeability (cm/s)
3.683 × 10
−4 c
Dose (mg)
80
Dose volume (mL)
250
Solubility at pH 4.37 (mg/mL)
0.025
d
Mean precipitation time (s)
900
e
Diffusion coeffi cient (cm
2
/s)
0.782 × 10
−5
a
Drug particle density (g/mL)
1.2
e
Effective particle radius (μm)
25
e
Body weight (kg)
74
FPE (liver) (%)
30
f
Blood/plasma conc. ratio
1
e
Unbound percent in plasma (%)
4.7
f
CL (L/h/kg)
0.012
f
V
c
(L/kg)
0.23
f
t
1/2
(h)
13.29
Simulation time (h)
48
Dosage form
IR tablet
a
in silico
predicted (ADMETPredictor™ module);
b
estimated by GastroPlus™ on the basis
of experimentally determined pH-solubility profi le;
c
value calculated on the basis of
in
vitro
measured permeability (CaCo
−2
cell line) (Stetinova et al., 2008) using permeability
converter integrated in GastroPlus™ software:
d
experimental value;
e
default
GastroPlus™;
f
literature value taken from Davis et al., 2000.
The predicted fraction of drug absorbed (F
a
) was 99.94%, which is in
accordance with the literature reporting almost 100% bioavailability of
GLK after oral administration (Delrat et al., 2002; Najib et al., 2002).
The predicted and
in vivo
observed PK parameters rendered percentage
prediction errors of less than 10% for C
max
and AUC values, indicating
that the model has predicted these parameters well. The largest deviation
was observed for t
max
(PE = 18.22%). However, considering variable
GLK
in vivo
kinetics (reported mean t
max
values after oral administration
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