3rd Meeting

Veterinary Toxicology

“Physiologically Based Pharmacokinetics Modelling”

Yos Adi Prakoso, DVM, MSc.

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 Physiology of Clostridium difficile

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 Physiologically Based Pharmacokinetics (PBPK)
Role in general Role in veterinary
• Mathematical • Used to improve the
simulation for prediction of toxicity
physiology in ADME of across species
toxin
• Used to predict • Used to predict effects
xenobiotic of exposure in differs
concentration and its route
risk

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 Advance role of PBPK

Measure concentration of toxin in organ target

Estimate time curve

Pathology stimulated

Chemical movement and

Chemical compartment and partitioning

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 Model construction I

Purpose of model should be determined

Diagram consist of tissue compartment

Plasma compartment

Another compartment that being suspected shows an effect

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 Full body model for
generic mammal
• Intravenous (IV), intramuscular
(IM), subcutaneous (SQ),
transdermal (TD), inhalational
(IH) and oral (PO).
• Ex represents excretion and
removal of the xenobiotic from
the body system. Solid line
arrows represent blood flow.
• Dashed line arrows represent
excretion processes. Dash-dot
line arrows represent
absorption processes

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 Full body model for
generic mammal
• Continuation….
• Schematic diagram of a generic
tissue block. Solid line arrows
represent blood flow.
• Dashed line arrows represent
excretion processes.

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 Model construction II
Diffusion of membrane-
Flow-limited model limited model
• Use for xenobiotic that • Use for large molecule
are small xenobiotic
• Use for lipophilic • Polar in nature
xenobiotic • Small blood flow to
• High blood flow to mass ratio
mass ratio

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 Equation in PBPK I

Basic mass balance for a flow-limited tissue compartment

• Qt= blood flow; Vt = anatomic volume; • Pt = tissue to blood partition

Ct = concentration of xenobiotic in
tissue. coefficient for tissue t
• Ca = concentration of xenobiotic in
arteri
• Cv = concentration of xenobiotic in vein

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 Equation in PBPK II
Basic mass balance for a membrane-limited tissue
compartment

• Ve= anatomic volume; Ce = xenobiotic concentration of extracellular space

in tissue t; Vi = volume intracellular space; Ci = concentration of xenobiotic
in intracellular space; Kt = membrane permeability coefficient for tissue t

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 Parameters in PBPK model

1. Blood flow
Physiology 2. Organ volume
3. Vascular space, etc

1. Partitioning
coefficient Physiochemical
2. Membrane
permeability
3. Rate of absorption 1. Protein binding
In vitro 2. Michaelis-Menton
constants

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 Results of analysis

Sensitivity analysis of
a few parameters in the
sulfamethazine (SMZ)
PBPK model showing
the relative
contributions to
venous blood
concentration of SMZ
from protein binding of
SMZ, hepatic
clearance, renal
clearance and protein
binding of acetyl-SMZ

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 Model validation
• Comparing model simulations to an external data set.
• It is important to exclude any data used in the
estimation of parameters in your external data set
• Simulations of the model are typically plotted along
side observed data points (simulation plots);
predicted values plotted versus observed values
(correlation plots) and residuals plotted against time
(residual plots)
• Results are then subjected to qualitative and
quantitative analysis for goodness of fit

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 Applications of PBPK for toxicologist
Predict toxin metabolite in
Predict concentration tissue
of toxin
Interaction between toxin and physiological
organ in processing of xenobiotics
Effects of toxin in
different species
Time course of xenobiotics

Extrapolation across different Pathological changes and sex of

route of exposure differences

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 Conclusions

1) PBPK models
provide a 2) It allows for the adaptability
continuously needed to simulate varied
evolving new physiological processes and
frontier in
toxicokinetic
PBPK biological system conditions

modeling
model
3) Assume an 4) Predict the consequences of
ever more exposure to toxins and its
important role in application in veterinary
our efforts to toxicology
understand

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Thank for your kind attention