Information Technology Reference
In-Depth Information
The overall concept of this strategy is illustrated in several papers
published by this group (Jones et al., 2006b; Parrott and Lave, 2008;
Parrott et al., 2009). For example, in one of these (Parrott et al., 2009),
GastroPlus™ PBPK absorption models for dog and human for two model
drugs (theophylline and aprepitant) were constructed in parallel by
integrating various predictive data, including drug physicochemical
properties, biorelevant solubility and dissolution, and
in vivo
study results.
Verifi cation of model assumptions was performed by comparing simulation
results to the food effects measured in carefully designed
in vivo
dog studies,
whereas a good match of simulated and observed plasma concentrations in
the fasted and fed dogs indicated that the model has captured well the
mechanisms responsible for food effects, allowing a reliable prediction for
humans. The results indicated that the strategy to predict food effects via
PBPK modeling highly depended on drug biopharmaceutical properties.
For theophylline, a BCS class I compound, the food effects for immediate
and CR formulations could be well simulated by default GastroPlus™
models for both dog and human. However, simulations for aprepitant, a
BCS II drug, required several changes to the default GastroPlus™ models
(e.g. adjustment of regional solubility data, modifi cation of the diffusion
coeffi cient used to calculate the dissolution rate), indicating that PBPK
modeling based on
in vitro
data for challenging drugs should be conducted
in conjunction with preclinical
in vivo
dog studies.
6.7
In vitro
dissolution and
in vitro-in vivo
correlation
There are two approaches enabling the GastroPlus™ generated drug-
specifi c absorption model to be used to assess the relationship between
the
in vitro
and
in vivo
data: convolution to predict the plasma
concentration profi le, and deconvolution to estimate the
in vivo
dissolution profi le. Once an IVIVC is developed, an
in vitro
dissolution
test can be used to identify changes that may affect the effi cacy and safety
of the drug product. In addition, biowaiver justifi cation could be discussed
in terms of whether dissolution from the dosage form is expected to be
the rate-limiting factor for drug
in vivo
absorption.
In the convolution approach, a set of
in vitro
data representing different
dissolution scenarios is used as the input function in GastroPlus™ software
to estimate the expected drug plasma concentration-time profi les. In the
next step, the obtained profi les are compared with the mean drug plasma
Search WWH ::
Custom Search