Transcript 01_Introduction

University of Jordan-Faculty of Pharmacy
Department of Biopharmaceutics and Clinical
Pharmacy
Semester:
First
Course Title:
Pharmacokinetics
Course Code:
1203475
Prerequisite:
Biopharmaceutics (1203471)
Instructor:
Dr. Mohammad Issa
Name
Office
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Office Hours
E - mail
Dr. Mohammad Issa
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Sun 12-1
Tue 11-12
[email protected]
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Course Objectives :
1) Understanding mathematical background for
modeling of the concentration time
relationships for the different routes of
administration.
2) Designing dosing regimens by relating
plasma concentration of drugs to their
pharmacological and toxicological action,
3) Understanding the concept of therapeutic
drug monitoring for drugs with narrow
therapeutic range or high toxicity.
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Learning Outcomes :
A)
Knowledge and understanding
A1) Understanding mathematics of the time course of
Absorption, Distribution, Metabolism, and Excretion
(ADME) of drugs in the body.
A2) Understanding Individualization of therapy and
therapeutic drug monitoring.
B)
Intellectual skills (cognitive and analytical)
B1) Utilization of mathematics of the time course of
Absorption, Distribution, Metabolism, and Excretion
(ADME) of drugs in the body for dosage optimization.
B2) Developing dosing regimens for the
individualization of therapy for the patient
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C)
Subject specific skills
C1) Fitting concentration time profiles and estimating
pharmacokinetic parameters.
C3) Designing dosing regimens in case of renal and
hepatic dysfunction.
D)
Transferable Skills
D1) Communicating the dosage adjustment with
physicians.
D2) Suggesting therapeutic monitoring plans.
Teaching Methods :
1)
Lectures
2)
Computer software (demo)
3)
Case Studies
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Tests & Evaluations :
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Midterm exam
Quizzes and HWs
Final exam
40%
10%
50%
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1. Introduction
2. The one-compartment open model with an intravenous bolus dose.
Plasma data; elimination rate constant, AUC, elimination half-life, volume
of distribution and clearance
Urinary data; excretion rate constant and half-life, elimination rate
constant
3. The one-compartment open model with an intravenous infusion.
Continues infusion, Infusion with a bolus dose, post infusion
4. The one-compartment open model with absorption and elimination;
Absorption rate constant, calculation of F, method of residuals, flip-flop
kinetics
5. The one-compartment open model with multiple dosing kinetics;
Multiple dosing IV and oral, multiple dosing factor, accumulation factor,
loading dose, and average concentration.
6. Designing dosing regimens
7. Dosage adjustment in renal failure. (Aminoglycosides)
8. The two-compartment open model with intravenous administration.
9. Non-linear pharmacokintics
Michaels-Mention kinetics, methods to obtain Vmax and Km (Phenytoin).
10. Pharmacodynamics
Linear models, E-max and time dependent response.
11. Therapeutic Drug Monitoring.
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12. Bioequivalence revisited.
Textbook:
Applied biopharmaceutics and pharmacokinetics
Shargel and Yu, 5th edition, 2005
References:
1) Pharmacokinetics: processes, mathematics, and applications
2nd edition, Welling, P.G.., 1997
2) Handbook of Basic Pharmacokinetics
Wolfgang Ritschel, 6th edition, 2004
3) Clinical pharmacokinetics: concepts and applications
Rowland and Tozer, 3rd edition, 1995
Useful Web Sites
1) PHARMACOKINETICS LECTURE NOTES ONLINE
http://www.healthsci.utas.edu.au/pharmacy/kinetics/main.htm
2) University of Alberta/ Dr. Jamali
http://www.pharmacy.ualberta.ca/pharm415/contents.htm
3) A First Course in Pharmacokinetics and Biopharmaceutics
http://www.boomer.org/c/p1/
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Pharmacokinetics: Introduction
Dr Mohammad Issa
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What is pharmacokinetics?
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What is pharmacokinetics?

Pharmacokinetics is the study of
kinetics of absorption, distribution,
metabolism and excretion (ADME)
of drugs and their corresponding
pharmacologic, therapeutic, or toxic
responses in man and animals’’
(American Pharmaceutical
Association, 1972).
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Review of ADME processes
ADME is an acronym representing
the pharmacokinetic processes of:
A  Absorption
D  Distribution
M  Metabolism
E  Excretion
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Review of ADME processes
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Absorption is defined as the process
by which a drug proceeds from the
site of administration to the site of
measurement (usually blood,
plasma or serum)
Distribution is the process of
reversible transfer of drug to and
from the site of measurement
(usually blood or plasma)
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Review of ADME processes
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Metabolism is the process of a
conversion of one chemical species
to another chemical species
Excretion is the irreversible loss of a
drug in a chemically unchanged or
unaltered form
Metabolism and excretion processes
represent the elimination process
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Applications of pharmacokinetics
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bioavailability measurements
effects of physiological and pathological
conditions on drug disposition and absorption
dosage adjustment of drugs in disease states, if
and when necessary
correlation of pharmacological responses with
administered doses
evaluation of drug interactions
clinical prediction: using pharmacokinetic
parameters to design a dosing regimen and thus
provide the most effective drug therapy
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Applications of pharmacokinetics
Bioavailability measurements: Blood sulfadiazine concentration in human
following the administration of a 3 g dose. A comparison of the behavior of
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microcrystalline sulfadiazine with that of regular sulfadiazine in human
Applications of pharmacokinetics
Effects of physiological and pathological conditions on drug
disposition and absorption: plasma conc-time profile of cefepime after
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a 1000 mg IV infusion dose
Applications of pharmacokinetics
Using pharmacokinetic parameters to design a dosing regimen
and thus provide the most effective drug therapy
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Rates and orders of reactions
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The rate of a chemical reaction of process is the velocity with which
the reaction occurs. Consider the following chemical reaction:
drug A  drug B
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If the amount of drug A is decreasing with respect to time (that is, the
reaction is going in a forward direction), then the rate of this reaction
can be expressed as
 dA
dt
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Since the amount of drug B is increasing with respect to time, the rate
of the reaction can also be expressed as
dB
dt
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The rate of a reaction is determined experimentally by measuring the
disappearance of drug A at given time intervals.
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Zero-Order Reactions
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Consider the rate of elimination of drug A
from the body. If the amount of the drug,
A, is decreasing at a constant rate, then
the rate of elimination of A can be
described as:
dA
 k *
dt
where k* is the zero-order rate constant.
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The reaction proceeds at a constant rate
and is independent of the concentration of
A present in the body. An example is the
elimination of alcohol
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Zero-Order Reactions
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The amount of a drug with zero order
elimination is described according to the
following equation:
A  A0  k * t
where A is the amount of drug in the
body, A0 is the amount of the drug at time
zero (equal to the dose in the case of IV
bolus)
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Drug with zero order PK
A0
Slope = -K*
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Zero-Order Reactions: example
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The administration of a 1000 mg of
drug X resulted in the following
concentrations:
0
Conc.
(mg/L)
100
4
90
6
85
10
75
12
70
Time
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Zero-Order Reactions: example
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What is the order of the elimination
process (zero or first)?
What is the rate constant?
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Zero-Order Reactions: example
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y = -2.5x + 100
R2 = 1
100
conc (mg/L)
80
60
40
20
0
0
2
4
6
8
10
12
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time (hr)
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Zero-Order Reactions: example
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Since the decline in drug conc. Displayed
a linear decline on normal scale, drug X
has a zero order decline
From the equation displayed on the figure
(intercept = 100, slope = -2.5)
The elimination rate constant is 2.5 mg/hr
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First-order Reactions
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If the amount of drug A is decreasing at a
rate that is proportional to A, the amount
of drug A remaining in the body, then the
rate of elimination of drug A can be
described as:
dA
 K  A
dt
where k is the first-order rate constant
The reaction proceeds at a rate that is
dependent on the concentration of A
present in the body
It is assumed that the processes of ADME
follow first-order reactions and most
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drugs are eliminated in this manner
First-Order Reactions
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The amount of a drug with first order
elimination is described according to the
following equation:
A  A0 e  k *t
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where A is the amount of drug in the
body, A0 is the amount of the drug at time
zero (equal to the dose in the case of IV
bolus)
This equation is equivalent to:
ln( A)  ln( A0 )  k * t
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Drug with first order PK
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Drug with first order PK:
log transformation
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Nonlinear kinetics
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Nonlinear pharmacokinetics is also known as
dose-dependent and concentration dependent
pharmacokinetics because the
pharmacokinetic parameters are dependent
on the drug concentration or the drug
amount in the body
At least one of the absorption, distribution,
and elimination processes, which affect the
blood drug concentration—time profile, is
saturable and does not follow first-order
kinetics
The change in drug dose results in
disproportional change in the blood drug
concentration— time profile after single- and
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multiple-dose administrations
Nonlinear kinetics
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Nonlinear kinetics
Nonlinear kinetics:
dC
C
 Vmax 
dt
Km  C
Linear kinetics:
dC
 K  C
dt
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Linear vs nonlinear PK
Linear PK
Nonlinear PK
1-Known as dose-independent or 1-Known as dose-dependent or
concentration-independent PK. concentration-dependent PK.
2-The absorption, distribution
and elimination of the drug
follow first-order kinetics
2-At least one of the PK processes
(absorption, distribution or
elimination) is saturable.
3-The pharmacokinetic
parameters such as the half-life,
total body clearance and volume
of distribution are constant and
do not depend on the drug conc
3-The pharmacokinetic
parameters such as the half-life,
total body clearance and volume
of distribution are concdependant
4-The change in drug dose
4-The change in drug dose results
results in proportional change in in more than proportional or less
the drug concentration.
than proportional change in the
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drug conc.
Laplace transformation
Optional material
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Laplace transformation
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The Laplace transform is a
mathematical technique used for
solving linear differential equations
(apparent zero order and first
order) and hence is applicable to
the solution of many equations used
for pharmacokinetic analysis.
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Laplace transformation procedure
1.
Write the differential equation
2.
Take the Laplace transform of each
differential equation using a few
transforms (using table in the next slide)
3.
Use some algebra to solve for the Laplace
of the system component of interest
4.
Finally the 'anti'-Laplace for the
component is determined from tables
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Important Laplace transformation (used
in step 2)
Expression
Transform
dX/dt
sX  X 0
K (constant)
K
s
X (variable)
X
K∙X (K is constant)
KX
where s is the laplace operator,
X is the laplace integral
, and X0 is the amount at time zero
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Anti-laplce table (used in step 4)
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Anti-laplce table continued (used in
step 4)
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Laplace transformation: example
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The differential equation that
describes the change in blood
concentration of drug X is:
dA
 k *
dt
Derive the equation that describe
the amount of drug X??
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Laplace transformation: example
1.
Write the differential equation:
dX
 k *
dt
2.
Take the Laplace transform of each
differential equation:
k*
sX  X 0  
s
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Laplace transformation: example
3.
Use some algebra to solve for the
Laplace of the system component
of interest
X0 k *
X
 2
s
s
4.
Finally the 'anti'-Laplace for the
component is determined from
tables
X (t )  X 0  k * t
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Laplace transformation: example

The derived equation represent the
equation for a zero order
elimination
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