Computer- aided biopharmaceutical characterization: gastrointestinal absorption simulation - Computer-Aided Applications in Pharmaceutical Technology - page 224

absorption rather than their dissolution. Overall, the obtained results
suggested that extending the biowaiver to include IR dosage forms of
BCS class III drug products is feasible, and moreover, that biowaivers for
BCS class III drug products with suitably rapid dissolution would ensure
'bioperformance' of these pharmaceutical products.
Crison et al. (2012) employed in silico modeling to justify biowaiver for
BCS class III drug metformin hydrochloride. GastroPlus™ modeling was
performed within the range of gastric transit times expected in human
subjects, to show the broad range of release rates that are expected to
have no impact on AUC and C max , and therefore result in drug products
BE. It should be noted that, although metformin exhibits nonlinear
pharmacrokinetics with respect to dose, the absorption model developed
in this study was based on 500 mg data, so the simulation results were
limited to that dose. Two clinical studies for IR formulations were used in
the model development and additional clinical studies, one for IR and one
for ER formulation, were used to confi rm that the model was predictive
over a wide range of drug release times. Drug release profi les representing
100% of metformin released in 5 min up to 14 h were used as inputs for
the model. The simulations to predict plasma concentrations of metformin
corresponding to different release rates were performed as virtual trials,
so that inter-subject variability could be introduced into the predictions.
In order to prove model predictability, the results of virtual trial simulations
(defi ned as 'test') were compared with the observed clinical data (defi ned
as 'reference'). According to the simulation results, metformin release
rates within 100% of drug, dissolved in 5 min up to 2 h did not have a
statistically signifi cant effect on C max and AUC 0-t . In addition, it was shown
that within this range of dissolution rates, metformin products are
expected to be bioequivalent, irrespective of the results of the f 2 test. In
conclusion, the results illustrated that the described in vitro-in silico
approach might be used to waive in vivo BE studies for metformin drug
product. Furthermore, it was deduced that in silico modeling and
simulation, which includes all the key parameters that fully defi ne the
absorption of BCS class III compounds (i.e. dissolution, permeability, and
GI residence time), should be more mechanistically accurate and robust
for BE evaluation than statistical comparison of in vitro release profi les.

￿

￿ ￿

6.9 Conclusions

The various examples presented demonstrate that GI modeling has become
a powerful tool to study oral drug absorption and pharmacrokinetics. This