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less than 0.2 mg/mL under the fasted state. However, since this border
value was within the reported range of aqueous solubility of CBZ, the
authors speculated that CBZ absorption is dissolution rate-limited rather
than solubility-limited. This assumption coincides well with our fi ndings
(Kovacevic et al., 2009) that CBZ
in vivo
solubility would not cause
bioavailability problems. PSA also denoted that permeability had
less effect on the predicted PK parameters (C
max
, t
max
, AUC
0-t
) when CBZ
was formulated as a suspension. As for the formulation factors, it was
shown that drug particle size and density had a signifi cant effect on CBZ
PK from IR formulations, being more pronounced in the case of IR
tablet in comparison to the IR suspension, but having no effect on drug
PK from XR formulations. However, the authors elucidated that this
occurred because in XR formulations the particle size effect was integrated
in the dissolution profi les, which were translated into Weibull functions
for input into the ACAT model. Another phenomenon observed was that
CBZ absorption profi les showed different sensitivity to the same factors,
depending on whether the PSA was performed for fasted state or fed
state. In general, it was shown that CBZ absorption profi les were more
sensitive to variations in input parameters tested in fasted state than in
fed state.
The work of Kuentz et al. (2006) is a good example of how PSA can be
used as an integral part of a strategy for preclinical formulation
development. In order to obtain detailed biopharmaceutical data on the
selected model drug, initially profi led to have poor solubility and high
permeability, GastroPlus™ simulations, together with the statistically
designed study in dogs, were conducted. In the fi rst step, the software
was used to simulate the absorption process based on pre-formulation
data. Then PSA was performed where drug particle size and solubility
values were varied (>100-fold range) and their impact on the oral
drug bioavailability was assessed. PK experiments in beagle dogs
were run according to the factorial design set-up to examine the effect of
the formulation in parallel with a potential food effect in a clinically
foreseen dose range. The obtained PSA results revealed that changes in
particle size and reference solubility in the investigated range would not
signifi cantly affect drug bioavailability (Figure 6.9), and the beagle
dogs study indicated that different dosage forms (solution and capsules
fi lled with micronized drug) were not expected to be signifi cantly
different in terms of AUC
0-inf
. Based on the fi ndings that particle size
reduction and/or solubility enhancement would not lead to increased
absorption, it was decided that there was no need to develop a
sophisticated drug delivery system; instead, capsule formulation was
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