494
N. Ya. Golovenko et al.
models and compartmental models. Both models can be linked to pharmacokinetic
models to predict plasma concentration-time profiles of drugs. The dispersion models defines the GI tract as a single tube with spatially varying properties ( pH, surface area, etc.). Instead of treating the small intestine as one long cylindrical tube in
a dispersion model, compartmental models assume the GI tract as one compartment
or a series of compartments with linear transfer kinetics, and each compartment is
well mixed with a uniform concentration. There have been several reports on physiologically based mathematical compartmental models (CAT, ACAT, Grass, GITA,
ADAM) that are capable of producing such predictions, and there are a few commercially available software packages (GastroPlusTM, IDEA™, INTELLIPHARM
PK, PK-SIM, etc.) that have been shown to predict the human absorption properties
with a fairly high degree of accuracy. As these models use the interplay between the
drug characteristics and the human physiology to simulate the processes involved
in the oral absorption of drugs, they also give information about the underlying
mechanisms for absorption limitations and as such they are well suited to be used in
progressing new chemistry and to support formulation development.
Study [84] has attempted to apply gastrointestinal simulation technology and integration of physiological parameters to predict biopharmaceutical drug classification. GastroPlus
®
was used with experimentally determined physico-chemical and
pharmacokinetic drug properties to simulate the absorption of several weak acid
and weak base BCS class 2 compounds. Simulation of oral drug absorption given
physico-chemical drug properties and physico-chemical parameters will aid justification of biowaivers for selected BCS class 2 compounds. In silico models are useful to identify BCS class 2 biowaiver candidate drugs. The risk of bioinequivalence
in terms of C max has shown to be higher than for AUC. Class 2 weak acids and bases
in immediate release dosage forms may be eligible for biowaivers provided that the
dose dissolves completely before reaching middle jejunum. Biowaivers for some
class 2 drugs also necessitate the availability of a discriminative and in vivo predictive in vitro dissolution method. Thus they should be complemented by prospective
IVIVC studies to validate the proper selection of biowaiver candidate drugs.
The in vivo absorbability of drugs categorized into the BCS class 2 is very difficult to predict because of the large variability in the absorption and/or dissolution
kinetics and the lack of an adequate in vitro system for evaluating the dissolution
behavior. Fujioka et al. [85] tried to predict the plasma concentration-time profile
of griseofulvin after oral administration into rats, based on GI-Transit-Absorption
model (GITA model). Griseofulvin, with ClogP = 2.88, was taken as a model drug
of BCS class 2, and the in vitro dissolution study was performed to evaluate the dissolution rate constant by employing several different dissolution media including
FaSSIF, FeSSIF and a couple of novel media. Using the dissolution rate constants
( k dis ) of griseofulvin obtained with JP 1st solution, JP 2nd solution, FaSSIF, FeSSIF,
and modified SIBLM as a medium, simulation lines were not able to describe the
observed mean plasma profile at all. On the other hand, a calculated line provided
by employing k dis obtained with MREVID 2 (medium reflecting in vivo dissolution
2), a new medium, was in better agreement with the observed mean plasma profile
than existing media.
N. Ya. Golovenko et al.
models and compartmental models. Both models can be linked to pharmacokinetic
models to predict plasma concentration-time profiles of drugs. The dispersion models defines the GI tract as a single tube with spatially varying properties ( pH, surface area, etc.). Instead of treating the small intestine as one long cylindrical tube in
a dispersion model, compartmental models assume the GI tract as one compartment
or a series of compartments with linear transfer kinetics, and each compartment is
well mixed with a uniform concentration. There have been several reports on physiologically based mathematical compartmental models (CAT, ACAT, Grass, GITA,
ADAM) that are capable of producing such predictions, and there are a few commercially available software packages (GastroPlusTM, IDEA™, INTELLIPHARM
PK, PK-SIM, etc.) that have been shown to predict the human absorption properties
with a fairly high degree of accuracy. As these models use the interplay between the
drug characteristics and the human physiology to simulate the processes involved
in the oral absorption of drugs, they also give information about the underlying
mechanisms for absorption limitations and as such they are well suited to be used in
progressing new chemistry and to support formulation development.
Study [84] has attempted to apply gastrointestinal simulation technology and integration of physiological parameters to predict biopharmaceutical drug classification. GastroPlus
®
was used with experimentally determined physico-chemical and
pharmacokinetic drug properties to simulate the absorption of several weak acid
and weak base BCS class 2 compounds. Simulation of oral drug absorption given
physico-chemical drug properties and physico-chemical parameters will aid justification of biowaivers for selected BCS class 2 compounds. In silico models are useful to identify BCS class 2 biowaiver candidate drugs. The risk of bioinequivalence
in terms of C max has shown to be higher than for AUC. Class 2 weak acids and bases
in immediate release dosage forms may be eligible for biowaivers provided that the
dose dissolves completely before reaching middle jejunum. Biowaivers for some
class 2 drugs also necessitate the availability of a discriminative and in vivo predictive in vitro dissolution method. Thus they should be complemented by prospective
IVIVC studies to validate the proper selection of biowaiver candidate drugs.
The in vivo absorbability of drugs categorized into the BCS class 2 is very difficult to predict because of the large variability in the absorption and/or dissolution
kinetics and the lack of an adequate in vitro system for evaluating the dissolution
behavior. Fujioka et al. [85] tried to predict the plasma concentration-time profile
of griseofulvin after oral administration into rats, based on GI-Transit-Absorption
model (GITA model). Griseofulvin, with ClogP = 2.88, was taken as a model drug
of BCS class 2, and the in vitro dissolution study was performed to evaluate the dissolution rate constant by employing several different dissolution media including
FaSSIF, FeSSIF and a couple of novel media. Using the dissolution rate constants
( k dis ) of griseofulvin obtained with JP 1st solution, JP 2nd solution, FaSSIF, FeSSIF,
and modified SIBLM as a medium, simulation lines were not able to describe the
observed mean plasma profile at all. On the other hand, a calculated line provided
by employing k dis obtained with MREVID 2 (medium reflecting in vivo dissolution
2), a new medium, was in better agreement with the observed mean plasma profile
than existing media.