Transcript Lectures 1 and 2 415..

PHT 415
BASIC PHARMACOKINETICS
Textbook:
Applied Biopharmaceutics and pharmacokinetics
Objectives of the first 2 lectures
(Introduction)
• To
understand
pharmacokinetic
applications.
and
define
parameters
the
and
basic
their
• To be familiar with the important pharmacokinetic
concepts
Introduction
• A simple definition of pharmacokinetics is
the study of the time course of drug
concentration in the body (what the body
does to the drug)
• Pharmacokinetic processes include
absorption, distribution, elimination
(metabolism and excretion)
Introduction
• Pharmacodynamics: The study of the
relationship between drug concentration in
the body and its pharmacological
response (what the drug does to the body)
Introduction
• Biopharmaceutics is the study of the
relationship between the physicochemical
properties of the drug, dosage form in
which the drug is given, and the route of
administration; and the rate and extent of
systemic drug absorption
Introduction
• Sites of drug administration may be
classified as intravascular or extravascular.
• Intravascular administration refers to the
placement of a drug directly into the blood,
either intravenously or intra-arterially.
• Extravascular include the oral, sublingual,
buccal, intramuscular, subcutaneous,
dermal, pulmonary, and rectal routes.
Introduction
• Drugs administered extravascularly must
be absorbed.
• Absorption may be defined as the
movement of drug molecules from the site
of administration to the blood circulation, in
order for a drug to be absorbed, it has to be
released from dosage form and converted
into solution.
Introduction
•
Disposition may be defined as the
processes that occur subsequent to the
absorption of a drug. Therefore, the
components of disposition are
distribution and elimination.
Introduction
• Once absorbed, a drug may be distributed
to the various organs of the body.
Distribution is influenced by the organ
blood perfusion, organ size, binding of
drug within blood and tissues, and
permeability of tissue membranes.
Introduction
• Distribution describes the reversible
diffusion or transfer of drug molecules
from intravascular space to body tissues.
• Elimination is the irreversible loss of drug
from the body by metabolism or excretion.
Introduction
• Metabolism describes the conversion of
drugs into metabolites by enzymes
(metabolites are usually more polar
compounds that are more easily excreted).
• The major site of metabolism is the liver
but it may occur in some other organs
such as intestines, lungs and kidneys.
Introduction
• Excretion is the irreversible loss of
chemically unchanged drug.
• The kidneys are the primary site for
excretion of most of the chemically
unchanged drugs. However, some drugs
are excreted by other routes such as the
bile.
Introduction
• Mass balance of a drug with time in the
body:
Dose = amount of drug at absorption site +
amount of drug in the body + amount of drug
eliminated (by metabolism and excretion)
Introduction
• Studying the pharmacokinetics of any drug
requires the measurement of drug
concentration in a suitable biological fluid
such as plasma, serum, blood or urine at
appropriate time intervals using a valid
analytical method (validation should cover
sensitivity, linearity, specificity, recovery,
accuracy, precision and stability)
Introduction
• The most direct and commonly used approach
for assessing drug pharmacokinetics is based
on the measurement of drug concentration in the
whole blood, serum or plasma.
• Serum is obtained by allowing the whole blood
to clot and the serum is collected from the
supernatant after centrifugation.
• Plasma is the supernatant of centrifuged whole
blood to which an anticoagulant, such as
heparin, was added.
Introduction
Plasma concentration - time curve:
• It Is generated by measuring the drug
concentration in plasma samples taken at
various time intervals after a drug product is
administered
• The concentration of drug in each plasma
sample is plotted against the corresponding
time at which the plasma sample was
collected.
Introduction
Introduction
Pharmacokinetic modeling:
• Mathematical models can be used to
describe drug absorption, distribution, and
elimination based on drug concentration (a
dependent variable) in the body as a function
of time (an independent variable).
Pharmacokinetic models may be used to:
• predict plasma , tissue, or urine drug levels
with any dosage form
• calculate the optimum dosage regimen for
each patient individually
• correct drug concentrations with
pharmacological or toxicological activity
• evaluate differences in the rate or extend
between formulations ( Bioequivalence
studies)
• study drug interactions
Event that follows drug administration
Plasm a Theophylline Concentration (m g/L)
6
5
4
3
2
1
0
0
12
24
36
48
Hours
Plasma conc of theophylline after an oral dose of 600-mg
Aimes of PK and PD
Knowing the PK and PD of drugs will aid
in designing a dosage regimen to achieve
the therapeutic objective.
OPTIMIZE PATIENT
DRUG THERAPY BY
MONITORING PK&PD
RESPONSES
Advantages over the Empirical
Approach
1- Distinction can be made between PK and
PD causes of an unusual drug response.
2- Information gained about the PK of one drug
can help in anticipating the PK of another drug.
3- Understanding the PK of a drug often
explains the manner of its use.
4- Knowing the PK of a drug aids the clinician
in determining the optimal dosage regimen for
a patient and in predicting what may happen
when a dosage regimen is changed.
An Approach to the Design of a Dosage
Regimen
Pharmacokinetics
Dosage
Regimen
Pharmacodynamics
Plasma
Concentration
Site
of
Action
Effects
Where to Measure Concentration?
Rarely can the concentration of the
drug at the site of action be
measured directly; instead, the
concentration is measured at an
alternative and more accessible
site, the plasma.
What is then an optimal
dosage regimen?
It is the one that maintains
the plasma concentration of a
drug within the therapeutic
window.
Therapeutic Window (TW)
 The size and frequency of the maintenance
dose depends on the width of the therapeutic
window and the speed of drug elimination.
 Generally, When the window is narrow and
the drug is eliminated rapidly, small doses
should be given more often to achieve
therapeutic success.
 Both cyclosporine and digoxin have a narrow
TW, but because cyclosporine is eliminated
much more rapidly than digoxin, it has to be
given more frequently.
Oxytocin
 Oxytocin is an extreme example, it also has
a narrow TW, but it is eliminated within
minutes. The only means to ensure a
therapeutic conc is to infuse it at a precise and
constant rate directly into the blood (i.v.
infusion). Oxytocin can not be given orally
because it is destroyed in the GIT.
 Morphine can not also be given orally
because it is extensively metabolized in the
liver.
PROBLEM!!!
Variability in Clinical Response
 Sources of variability include: patient’s
age, weight, type and severity of disease, the
patient’s genetic makeup, other drugs
concurrently administered.
 Result: A standard dosage regimen of a
drug may prove therapeutic in some patients,
ineffective or even toxic in others.
Dosage Regimen Adjustment
Especially for drugs with narrow TW such
as:
 Digoxin
Phenytoin
Theophylline
Cyclosporine
Warfarin
Drug-Drug Interaction
Interactions that result in a change in PK of
a drug could be due to interference with :
drug absorption.
drug distribution.
drug excretion.
drug metabolism.
WHAT WE WILL DO IN
THIS CLASS?
 Although the details of drug kinetics are
complicated, it is fortunate that we can often
approximate drug kinetic processes using
“SIMPLE MATHEMATICAL MODELS”.
 The use of PK equations, rather than the
derivation of the equations will be taught in
this class.