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
#

Office Hours

E - mail

Dr. Mohammad Issa

230

Sun 12-1
Tue 11-12

[email protected]

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.
2

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
3

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
4

Tests & Evaluations :

Midterm exam
Quizzes and HWs
Final exam

40%
10%
50%

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.
6
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/
7

Pharmacokinetics: Introduction

Dr Mohammad Issa

What is pharmacokinetics?

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).

10

Review of ADME processes

ADME is an acronym representing
the pharmacokinetic processes of:
A Absorption
D Distribution
M Metabolism
E Excretion

11

Review of ADME processes

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)
12

Review of ADME processes

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
13

14

Applications of pharmacokinetics

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

15

Applications of pharmacokinetics

Bioavailability measurements: Blood sulfadiazine concentration in human

following the administration of a 3 g dose. A comparison of the behavior of
16
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
17
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

18

Rates and orders of reactions

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

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

Since the amount of drug B is increasing with respect to time, the rate
of the reaction can also be expressed as

dB
dt

The rate of a reaction is determined experimentally by measuring the

disappearance of drug A at given time intervals.

19

Zero-Order Reactions

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.

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
20

Zero-Order Reactions

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)

21

Drug with zero order PK

A0

Slope = -K*

22

Zero-Order Reactions: example

The administration of a 1000 mg of

drug X resulted in the following
concentrations:
Time
0
4
6
10
12

Conc.
(mg/L)
100
90
85
75
70

23

Zero-Order Reactions: example

What is the order of the elimination

process (zero or first)?
What is the rate constant?

24

Zero-Order Reactions: example

120

y = -2.5x + 100
2
R =1

100

conc (mg/L)

80

60

40

20

0
0

10

12

14

time (hr)

25

Zero-Order Reactions: example

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

26

First-order Reactions

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 rate
A constant
where k is the first-order
dt

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 drugs are
eliminated in this manner

27

First-Order Reactions

The amount of a drug with first order

elimination is described according to the
following equation:

A A0 e 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)
This equation is equivalent to:

ln( A) ln( A0 ) k * t
28

Drug with first order PK

29

Drug with first order PK:

log transformation

30

Nonlinear kinetics

Nonlinear pharmacokinetics is also known as dosedependent 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
concentrationtime 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 multiple-dose
administrations
31

Nonlinear kinetics

32

Nonlinear kinetics

Nonlinear kinetics:

dC
C
Vmax
dt
Km C
Linear kinetics:

dC
K C
dt

33

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
34
drug conc.

Laplace transformation
Optional material

35

Laplace transformation

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.

36

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
37

Important Laplace transformation (used

in step 2)
Expression

Transform

sX X 0

dX/dt
K (constant)

K
s

X (variable)

KX (K is constant)
where s is the laplace operator,

KX
X is the laplace integral

, and X0 is the amount at time zero

38

Anti-laplce table (used in step 4)

39

Anti-laplce table continued (used in

step 4)

40

Laplace transformation: example

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??
41

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

42

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

43

Laplace transformation: example

The derived equation represent the

equation for a zero order
elimination

44

45