COMPUTER AIDED BIOPHARMACEUTICAL CHARACTERIZATION

INTRODUCTION:
Biopharmaceutical assessment of drugs is of crucial importance in different
phases of drug discovery and development. In early phases, pharmaceutical
profiling can help to find an appropriate ‘drug- like’ molecule for preclinical
and clinical development, and in later stages, extended biopharmaceutical
evaluation can be used to guide formulation strategy or to predict the effect of
food on drug absorption. A growing concern for biopharmaceutical
characterization of drugs/pharmaceutical products increased the interest in
development and evaluation of in silico tools capable of identifying critical
factors (i.e. drug physicochemical properties, dosage form factors) influencing
drug in vivo performance, and predicting drug absorption based on the selected
data set(s) of input factors.
Although an in silico pharmacokinetic (PK) model can confirm different drug
administration routes, the main focus has been on prediction of
pharmacokinetics of orally administered drugs. Drug absorption from the
gastrointestinal (GI) tract is a complex interplay between a large number of
factors (i.e. drug physicochemical properties, physiological factors, and
formulation related factors), and its correct representation in the in silico models
has been a major challenge. Various qualitative/quantitative approaches have
been proposed, starting from the pH-partition hypothesis, and later moving to
the more complex models, such as the Compartmental Absorption and Transit
(CAT) model.
In recent years, substantial effort has been allocated to develop and promote
dynamic models that represent GI tract physiology in view of
 drug transit,
 dissolution, and
 absorption.
Among these are the
 Advanced Dissolution,
 Absorption and Metabolism (ADAM) model,
 the Grass model,
 the GITransit-Absorption (GITA) model,
 the CAT model, and
 the Advanced CAT (ACAT) model.
Some of them have been integrated in commercial software packages, such as
GastroPlus™, SimCYP, PK-Sim®, IDEA™ (no longer available), Cloe® PK,
Cloe® HIA, and INTELLIPHARM® PKCR. One of the first overviews of the
available software intended for in silico prediction of absorption, distribution,
metabolism, and excretion (ADME) properties was given in the report of
Boobis et al. (2002). Cross-evaluation of the presented software packages was
interpreted in terms of software purpose and function, scientific basis, nature of
the software, required data to run the simulations, performance, predictive
power, user friendliness, flexibility, and evolution possibilities.
Due to dynamic interpretation of the processes a drug undergoes in the GI tract,
dynamic models are able to predict both the fraction of dose absorbed and the
rate of drug absorption, and can be related to PK models to evaluate plasma
concentration-time profiles (Yu et al., 1996). Such models can be beneficial at
different stages of formulation development. For example, taking into account
all the relevant biopharmaceutical properties of the compound of interest, the
potential advantage of various drug properties in terms of improving oral
bioavailability can be in silico assessed, before proceeding to in vivo studies.
Also, by providing more mechanistic interpretation of PK data, these models
can be utilized to explore mechanistic hypotheses and to help define a
formulation strategy. The effect of food on drug absorption or possible impact
of intestinal transporters and intestinal metabolism can be explored, leading to a
better understanding of the observed pharmacokinetics, and guiding subsequent
formulation attempts to reduce these effects.
The decisive advantage of in silico simulation tools is that:
 they require less investment in resources and
 time in comparison to in vivo studies.
 they offer a potential to screen virtual compounds.
 Reduce the number of experiments, and concomitant costs and time
required for compound selection and development.
 In addition, in silico methods can be applied to predict oral drug
absorption when conventional PK analysis is limited, such as when
intravenous data are lacking due to poor drug solubility and/or if the drug
shows nonlinear kinetics.

Theoretical background
Simulation software packages, such as GastroPlus™, are advanced technology
computer programs designed to predict PK, and optionally, pharmacodynamic
effects of drugs in humans and certain animals. The underlying model in
GastroPlus™ is the ACAT model, an improved version of the original CAT
model. This semi-physiological absorption model is based on the concept of the
Biopharmaceutics Classification System (BCS) and prior knowledge of GI
physiology, and is modeled by a system of coupled linear and nonlinear rate
equations used to simulate the effect of physiological conditions on drug
absorption as it transits through successive GI compartments.
The ACAT model of the human GI tract
 It was developed based on the CAT model.
 This model includes linear transfer kinetics and non-linear
metabolism/transport kinetics.
 Six states of drug component (unreleased, undissolved, dissolved,
degraded, metabolized and absorbed).
 Nine compartments (stomach, seven segments of small intestine and
colon)
 Three states of excreted material (unreleased, undissolved, dissolved).
 It takes into consideration physicochemical factors (pka, solubility,
particle size, particle density, and permeability).
 Physiological factors (gastric emptying, intestinal transit rate, first-pass
metabolism, and luminal transport).
 Dosage factors (dosage form and dose)in predicting oral drug absorption.
In general, the rate of change of dissolved drug concentration in each GI
compartment depends on ten processes:
ACAT model interpretation of in vivo drug behaviour:
I) transit of drug into the compartment;
II) transit of drug out of the compartment;
III) release of drug from the formulation into the compartment;
IV) dissolution of drug particles;
V) precipitation of drug;
VI) luminal degradation of drug;
VII) absorption of drug into the enterocytes;
VIII) exsorption of drug from the enterocytes back into the lumen;
IX) absorption of drug into portal vein via paracellular pathway; and
X) exsorption of drug from portal vein via paracellular pathway.

The ACAT model successfully predicted oral absorption for drugs undergoing
 first-pass hepatic metabolism (propranolol)
 first-pass intestinal & hepatic metabolism (midazolam)
 efflux transport (digoxin) and
 first pass metabolism plus efflux transport (saquinavir)