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80% in 45 min) were designed and used to predict plasma concentrations
vs. time and absorption curves for each compound used in the simulations.
Depending on the drug properties, either GastroPlus™ Single Simulation
Mode or Virtual Trial (e.g. for verapamil, which is a highly variable drug)
were selected for the simulations. PSA was performed in order to assess
the infl uence of drug properties (i.e. particle size, solubility, precipitation
time) on the fraction of drug absorbed. According to the obtained results,
and supported by previously published biopharmaceutical data on the
selected model drugs, it was deduced that ibuprofen, ketoprofen,
diclofenac, piroxicam, and terbinafi ne could be considered as candidates
for biowaiver. However, GI simulation indicated that mefenamic acid
and miconazole were not eligible for granting a biowaiver. According to
the predictions, mefenamic acid exhibited solubility and dissolution
limited absorption in the small intestine. Moreover, this drug lacked a
predictive dissolution method which would indicate its biopharmaceutical
properties. In the case of miconazole, it was found that oral drug
absorption was limited by dissolution rate and by the saturated solubility,
indicating that a highly dosed drug would probably precipitate in the
GI milieu.
Tsume et al. (2010) investigated the ability of GIST to predict oral
absorption of the selected BCS class I (propranolol and metoprolol) and
BCS class III drugs (cimetidine, atenolol, amoxicillin), and performed
in silico
BE studies to estimate the feasibility of extending biowaivers to
BCS class III drugs. In addition, the signifi cance of 'rapid dissolution' and
'very rapid dissolution' criteria for BCS class III drugs was evaluated. The
GastroPlus™ Virtual Trial model was used to assess the infl uence of drug
dissolution kinetics on oral drug absorption, C
max
, AUC, and BE. A set of
virtual
in vitro
dissolution data (corresponding to 85% release in 15, 30,
45, 60, 90, 120, and 180 min) was used as input function in GastroPlus™
to predict the drug PK profi le. For each BCS class III drug, virtual trial
(500 subjects) with T
85%
= 15 min ('very rapid dissolution'), and virtual
trials (24 subjects) at different release rates (from T
85%
= 30 min to T
85%
=
180 min) were performed as 'reference' and 'samples', respectively. The
results of the predictions (mean C
max
and AUC
0-inf
± SDs), with different
release rates used as 'samples,' were compared with the reference results
to determine BE. The results demonstrated BE up to T
85%
= 45 min (for
amoxicillin) or T
85%
= 60 min (in the cases of cimetidine and atenolol)
compared to the reference result of T
85%
= 15 min, including BE between
very rapid (>85% solubility in 15 min) and rapid dissolution (>85%
solubility in 30 min). These fi ndings indicated that the permeability of
BCS class III compounds was the rate-limiting step for oral drug
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