Gastrointestinal absorption

simulation
 Gastrointestinal absorption
simulation- Significance

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.
 Variable Models

 Advanced Dissolution, Absorption and

Metabolism (ADAM) model,
 Grass model, the GI-Transit-absorption
(GITA) model,
 CAT model, and the Advanced CAT (ACAT)
model Some of them have been integrated in
commercial software packages, such as
GastroPlus™,
 Outcome of Model- Advantages

 potential advantage of various drug properties in

terms of improving oral bioavailability can be in silico
assessed, before proceeding to in vivo studies.
 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.
 Advantages …

 less investment in resources and time in

comparison to in vivo studies.
 Virtual compounds.
 The number of experiments, and concomitant
costs and time required for compound
selection and development, is considerably
reduced.
 Applied to predict oral drug absorption when
 Theoretical background

 Biopharmaceutics Classifi cation System

(BCS)
 GI physiology.
 The ACAT model of the human GI tract
consists of nine compartments linked in
series.
 Drug concentration in each GI
compartment depends…?
 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. lumenal 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.
 Calculation of parameter

 Transfer rate constant (kt),

 dissolution rate constant (kd)
 Absorption rate constant (ka)
 Lumenal degradation rate constant (kdegrad)
 Model construction input parameter

 Default physiology parameters under fasted and fed

states
 (e.g. transit time, pH, volume, length, radii of the
corresponding GI region).
 The other input parameters include drug physicochemical
properties (i.e. solubility, permeability, logP, pKa, diffusion
coeffi cient) and PK parameters (clearance (CL), volume of
distribution (Yc), percentage of drug extracted in the oral
cavity, gut or liver, etc.), along with certain formulation
characteristics (e.g. particle size distribution and density,
drug release profiles for controlled-release formulations).
 Analysis

 Model 1 outcomes indicated involvement of influx transporters in

nimesulide absorption, while according to the
 Model 2 outcomes, the pH-surfactant induced increase in drug
solubility was a predominant factor leading to relatively rapid
absorption in the proximal intestine. It should be noted that the
Model 2 assumption was supported by the concept of
Biopharmaceutics Drug Disposition Classifi cation System
(BDCCS), according to which BCS class II drugs are not
expected to be substrates for influx transporters .
 In addition, parameters for which accurate data were not
available (i.e. in vivo solubility and human jejunal permeability)
were optimized in Model 2.
 Parameter sensitivity analysis

 one parameter is changed gradually within a

predetermined range, which should be based
on prior knowledge, while keeping all other
parameters at baseline levels. Another option
is to use three-dimensional PSA when two
parameters are varied at a time, so the
combined effect of these parameters is
assessed. In addition, an optimized design
space can be constructed as a function of the
selected parameters.
 Another useful application of this feature
concerns highly variable drugs, where PSA can
predict the effect of inter- individual
variation in PK parameters on drug absorption.
PSA can also be used to guide formulation
design.
 Virtual trial

 stochastic simulations on a number of virtual

subjects, wherein the values of the selected
variables are randomly sampled from
predetermined distributions (defi ned as
means with coeffi cients of variation (CV%) in
absolute or log space).
 Fed vs. fasted state

 The food effect for each drug was estimated

by comparing AUC or Cmax between fasted,
fed, and/or high-fat conditions. Predicted and
observed plasma concentration-time profi les
and food effects were compared for a range
of doses to assess the accuracy of the
simulations
 In vitro dissolution and in vitro-in vivo
correlation
 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.
 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
concentration profi le observed in vivo, in
order to establish an IVIVC.
 In the deconvolution approach, the
GastroPlus™ generated in vivo dissolution
profi le is plotted against the in vitro
obtained dissolution profi les, so that
'bioperformance' dissolution condition(s) can
be identifi ed.
 Biowaiver considerations

 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 profiles.
 Computer Simulation in Pharmacokinetic and
Pharmacodynamic Studies
 WHOLE ORGANISM:
I. The first approach is through the
formalization of a lumped-parameter PK-PD
model
1.The first approach is through the
formalization of a lumped-parameter PK-PD
model , often coupled with a model of the
disease process , whose parameters can be
estimated from data.
 2. by using models to generate synthetic data,
ultimately performing a full clinical trial
simulation from first principles
 II. The other approach to whole organism
models is based on physiological modeling ,
brought into practice by physiologically based
pharmacokinetic (PBPK) models
 The approach taken by PBPK modeling is not
very dissimilar from the recently proposed
Physiome Project
 PKPD Model

 Paracetamol
 Pharmacokinetic and dynamic model was applied to
predict the dosing schedule of paracetamol to
maintain the steady state plasma concentration. The
study is based on the study of children aged 1 to 17
years.
 Computer modelling using pharmacokinetic dynamic
simulation with MKMODEL program
 70mg/kg loading dose and 50mg/kg maintenance dose
was predicted by simulation to achieve the
satisfactory therapeutic effect
 Meropenem
 Meropenem is a carbapenem antibiotic with a very broad
spectrum of activity that makes it a good choice for the
empirical therapy situation.
 Pharmacokinetic calculations were done by use of a two-
compartment open model. The study was done for two doses.
Monte Carlo simulations for 10,000 simulated subjects for
pharmacodynamic evaluation
 high-dose continuous infusion has a robust probability of target
attainment up to an MIC of 4 mg/ litre. The lower-dose
probability of target attainment is still robust up to an MIC of 2
mg/litre
 CNS drug (R1315)
 Oral bioavailability prediction was studied as a
function of the particle size and drug solubility.
 Computer simulations were performed with the
software Gastro Plus TM V.4.0 (Simulations Plus Inc.,
Lancaster, USA), Simulation together with the
statistically designed dog study provided a thorough
biopharmaceutical assessment of the new CNS drug.
 ISOLATED TISSUES AND ORGANS

 National Institute for General Medical Sciences at

the NIH, the Center for Modeling Integrated
Metabolic Systems (MIMS) , has as its mission the
development and integration of in vivo, organ-specific
mathematical models that can successfully predict
behaviors for a range of parameters, including rest
and exercise and various pathophysiological
conditions. The Microcirculation Physiome and the
Cardiome are other multicenter projects focused on
particular aspects of the Physiome undertaking.
 ISOLATED TISSUES AND ORGANS

bloodtissue exchange (BTEX) models

 Insulin

 subcutaneous (SC) insulin absorption model

for computer simulation in a clinical diabetes
 AIDA insulin PK model

 Ability of the model to capture the

fundamental dynamics of insulin action for
several insulin types based on data from a
wide range of studies using a unified
consistent PK model.
 COMPUTER SIMULATIONS OF THE
CELL
 optimal design of bioreactors and, more in
general, for how biological systems may
choose to adapt in the face of changing
environments.
 Virtual Cell
 CellML
 mechanistic model of the intracellular metabolism of
methotrexate , which was then merged in an
integrated model of in vitro and in vivo information.
 Corticosteroids
 Corticosteroid pharmacokinetics in the cochlear
fluids for inner ear disorders.
 Simulated with a finite element computer model, the
Washington University Cochlear Fluids Simulator,
version 1.6
 The application protocol has a significant effect on
the drug levels achieved in per lymph, with different
delivery strategies resulting in very different
amounts of drugs in the per lymph
 PROTEINS AND GENES

 The success story of antiretrovirals testifies

to that concept. At the same time, one of the
most interesting contributions of computer
simulation to pharmacotherapy was also in the
field of HIV/AIDS treatment, through the
development of models of HIV viral load
based on clinical data.
 PROTEINS AND GENES

 Methylprednisolone
 Computer simulations allow application protocols
and drug delivery systems to be evaluated, and may
permit animal studies to be extrapolated to the
larger cochlea of the human.
 3D model was implemented in a commercial software
package for finite-element calculations (ANSYS ®,
ANSYS Inc., Canonsburg Pa., USA)
 3D computations demonstrate the existence of
substantial gradients across the scale in the basal
turn.
 Computational fluid dynamics

 Applications
The prediction and modeling of flows in
vascular and pulmonary systems on a patient-
specific basis is still an obstacle, but it is
becoming more likely that CFD will find its
place in enhanced diagnosis and planning of
surgical procedures.
 CFD simulations may give valuable information regarding
characteristics of blood flow under complex flow
conditions, as well as deformation and flow of
erythrocytes in microcirculation.
 CFD might be a powerful tool for patient-specifi c
simulation of blood flow inside the abdominal aorta
bifurcation or it might be used to explain variable
incidence of vascular dysfunction among patients with
surgically repaired coarctation of the aorta.
 Diagnosis and treatment of cerebral aneurysms.
 CFD can serve as an effective tool in clarifying the fl ow
patterns in the airways of patients suffering from this
disease and may provide useful information regarding
treatment
 Application of CFD in pharmaceutical technology
 CFD has been recognized as a promising tool for the
analysis and optimization of various pharmaceutical
unit operations, process equipment, drug delivery
devices, quality control equipment.
 Application of CFD methods in pharmaceutical
product and process development may lead to better
process understanding, reduced number of
experiments, and reduced cost and time savings
 Inhaler development

Schematic representation of different

grid structures:
(a) full grid case; (b) grid case 1; and (c)
grid case 2
CFD simulated particle tracks of
dispersed powder:
(a) full grid case; (b) grid case 1; and
(c) grid case 2
Carrier particle trajectory inside the
inhaler at 60 L/min
(from left, dparticle = 32, 108, and 275 μm):
(a) Aerolizer®,
(b) Handihaler
CFD simulations of fl
uid fl ow: (a) below the
paddle in the USP
dissolution apparatus
at 50 rpm; and (b) in
the USP dissolution
apparatus with a
compact of 8.5 mm
height situated at the
base of the vessel
Path-lines of fl uid fl
ow tracked with time
for 5 seconds from an
initial plane 0.5 mm
above the base of the
USP paddle dissolution
vessel at 25, 50, 100,
and 150 rpm
Photograph of compact after undergoing
dissolution for 1 h in: (a) position 1 and
(c) position 2. Velocity vectors
surrounding the compact in: (b) position 1
and (d) position 2. Left side of the
compact in (a) and (b) is facing the
center of the base of the vessel; the
front of the compact in (c) and (d) is
facing the center of the base of the
vessel
Contours of velocity magnitude around
the basket at 50 rpm