Computer- aided biopharmaceutical characterization: gastrointestinal absorption simulation - Computer-Aided Applications in Pharmaceutical Technology - page 222

addition, in vitro results indicated that GLK solubility and dissolution
from IR tablets are not expected to be the rate-limiting factors for GLK
in vivo absorption, and since this was a highly permeable drug, there was
a rationale to postulate that biowaiver extension might be applicable in
the case of GLK IR tablets (Grbic et al., 2011).
Another example is the work of Okumu et al. (2009), who combined
in vitro results with in silico simulations using GastroPlus™, in order to
support biowaiver for IR etoricoxib solid oral dosage forms. They used
in vitro measured solubility and dissolution data in different media, along
with caco −2 assessed drug permeability as input functions in the program
in order to predict etoricoxib absorption profi le. The simulation results
revealed that drug absorption after tablet administration was similar to
the absorption of an oral solution, indicating fast and complete drug
absorption. Furthermore, solubility results indicated etoricoxib behaves
like a BCS class I drug in an acidic environment, and the dissolution
transfer model confi rmed that the drug stays in solution when transferred
from the acidic environment of the stomach into the small intestine.
Therefore, it was concluded that etoricoxib might be a suitable candidate
for biowaiver.
In our CBZ study (Kovacevic et al., 2009), biowaiver justifi cation for
this BCS class II drug was elaborated upon. The GastroPlus™ generated
CBZ-specifi c absorption model was used to predict drug plasma
concentration-time profi les based on different in vitro dissolution rates as
input function. The results revealed that high dissolution rates (i.e. >85%
of drug dissolved in <10 min) were not related to the signifi cant increase
in C max in comparison to the in vivo observed values, thus indicating
that the predicted plasma concentration profi les were rather insensitive
to the differences in drug input kinetics. Following these results, it
was concluded that there is a rationale for considering CBZ biowaiver
extension. However, it was stressed that, at present, other factors such as
CBZ narrow therapeutic index and vital indication are the limitations for
granting marketing authorization based on the in vitro data alone.
Tubic-Grozdanis et al. (2008) also demonstrated that GI simulation of
oral drug absorption can aid in identifi cation of BCS class II biowaiver
candidate drugs. They used several weakly acidic (i.e. ibuprofen,
ketoprofen, diclofenac, mefenamic acid, and piroxicam) and weakly
basic (i.e. verapamil, miconazole, and terbinafi ne) BCS class II model
compounds, and GIST as a tool to study how differences in dissolution
rates would affect drug bioavailability and other PK properties.
Theoretical dissolution profi les of two IR drug products, namely 'rapid
IR' (released >90% of the dose within 10 min) and 'slow IR' (released

￿

￿ ￿