1. Introduction and Basic PK (1).ppt and

1
Clinical Pharmacokinetics
Part two

Quiz (10%)
3 point each
1.Write methods of assessing bioavailability with
example
2.Write at least three methods used to improve
solubility of poorly soluble drugs
3.Write at least three application of PK studies.

Part-II: Clinical Pharmacokinetics
• Introduction
– Definitions, applications and types of PKs
– PK and PD relationships
• Basic Pharmacokinetics
– Order and rate constants
– Pharmacokinetic models
– Drug distribution, metabolism, and elimination
• Clinical pharmacokinetics
– Definition and Applications
– Individualization and optimization of drug therapy
– Therapeutic drug monitoring

Define Pk
Discuss the areas and applications of Pk
Compare zero order and 1st
order kinetics
Define PK models
Analyse one & two compartment open models
Explain physiologic model
Differentiate compartmental models and physiologic
models
Learning Objectives

Derived form two Greek words:
Pharmakon drug
Kinesis  motion or change of rate
The study and characterization of the time course of
drug ADME and the relationship of ADME processes to
the intensity and the time course of therapeutic and
toxicologic effects of drug

Clinical PK
The application of PK principles to the safe and effective
therapeutic management of drugs in an individual Pt
Goals
Enhancing efficacy
Decreasing toxicity
Scope
Drug dosing in special population
TDM
Importance
70 to 80% of ADRs are dose related

Population PK…….Reasoning of differences in therapeutic
response of drugs in various population groups
Age, gender, genetic, ethnic, etc
Toxicokinetics…….. is the application of PK principles to the
design, conduct, and interpretation of drug safety
evaluation studies and in validating dose-related exposure
in animals.
Toxicokinetic data aids in the interpretation of
toxicologic findings in animals and extrapolation of
the resulting data to humans.

Applications of PK studies include;
BA 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 PK parameters to individualize the drug
dosing regimen and thus provide the most
effective drug therapy.

Absorption: the process by which a drug proceeds from
the site of administration to the site of measurement
(usually blood, plasma or serum).
Distribution: the process of reversible transfer of drug
to and from the site of measurement.
Any drug that leaves the site of measurement and does
not return has undergone elimination.

The rate and extent of drug distribution is determined by:
How well the tissues and/or organs are perfused with blood
The binding of drug to plasma proteins and tissue
components
The permeability of tissue membranes to the drug molecule.
These factors are determined by physicochemical properties and
chemical structures (i.e. presence of functional groups) of a drug
molecule.

Metabolism: the process of conversion of one chemical
species to another chemical species.
Usually, metabolites will possess little or none of the
activity of the parent drug.
However, there are exceptions.
Examples of drugs with therapeutically active metabolites:
Procainamide (antidysrhythmic agent) to N-acetyl procainamide
Propranolol HCl (non-selective β-antagonist) to 4-hydroxypropranolol
Diazepam (anxiolytic-sedative) to desmethyldiazepam

Elimination: the irreversible loss of drug from the site
of measurement.
Elimination of drugs occur by one or both of
metabolism or excretion.
Excretion……………..the irreversible loss of a drug

The two principal organs responsible for drug elimination
are the kidney and the liver.
The kidney is the primary site for removal of a
drug in a chemically unaltered or unchanged form
(i.e. excretion) as well as for metabolites
The liver is the primary organ where drug
metabolism occurs

The lungs, occasionally, may be an important route
of elimination for substances of high vapor
pressure (i.e., gaseous anesthetics, alcohol, etc).
Another potential route of drug removal is a
mother’s milk.
Although not a significant route for elimination of a
drug for the mother, the drug may be consumed in
sufficient quantity to affect the infant.

Disposition.….is defined as all the processes that
occur subsequent to the absorption of the drug.
By definition, the components of the disposition phase
are distribution and elimination.
Once a drug is in the systemic circulation, it is
distributed simultaneously to all tissues including the
organ responsible for its elimination.

PK describes what the body does to the drug (ADME)
PD measures what the drug does to the body
(therapeutic and/or toxic effect).
The entire science of PK is predicted on the observation
that, for most drugs, there is a correlation between drug
response and drug concentration in the plasma.
This correlation is not, however, a linear one.
In fact, for most drugs, a sigmoidal (S-shaped) relationship
exists between these two factors.

The therapeutic effect
reaches a plateau,
where increase in
drug concentration
will have no further
increase in effect.

 In contrast, the toxic
effects of a drug show no
such plateau.
 Toxic effects start at the
MTC and continue to rise,
without limit, as drug
concentration increases

The best measure of a drug’s activity at any given time would
be obtained from a direct and quantitative measurement of
the drug’s therapeutic effect.
This is possible for a few drugs;
For example, the effect of an antihypertensive drug is best
measured by recording the Pt’s BP.
However, for the large majority of drugs whose effect
is not quantifiable, the plasma drug concentration
remains the best marker of effect.

For some drugs,
We can link the parameters and equations of PK
to those of PD,
Resulting in a PK-PD model which can predict
pharmacological effect over time

Rate
The speed with which the reaction/process occurs
Is the velocity with which the reaction occurs.
Drug A  Drug B
Rate = -dA/dt = +dB/dt
The amount of drug A is decreasing with
respect to time
The amount of drug B is increasing with
respect to time

Order
How conc. or amount of the drug influences the
rate of a process
Zero order, first order, ….
Half-Life
Half-life (t 1/2) expresses the period of time required
for the amount or concentration of a drug to
decrease by one-half.

Rate is independent of the remaining
concentration/amount
dA/dt = -Ko
Ko
The zero-order rate constant
Expressed in units of mass/time (eg, mg/min)
Integration
A = -Kot + Ao
A0 & A are the amount of drug at t = 0 & time t
Some kinetic processes in the body follow zero order

Graph of A versus t yields a straight
line
The y intercept is equal to A0, and
the slope of the line is equal to -k0
Zero-Order Half-Life (t1/2)
t1/2 = 0.5Ao/Ko

In terms of drug concentration, which can be
measured directly, the above equation can be
expressed as:
C0 is the drug concentration at time 0,
C is the drug concentration at time t, and
k0 is the zero-order decomposition constant.

A Pharmacist weighs exactly 10g of a drug and dissolves it in 100mL of water. The solution is
kept at room temperature, and samples are removed periodically and assayed for the drug.
The pharmacist obtains the following data. Calculate zero order rate constant.
Drug Concentration (mg/mL) Time (hr)
100 0
95 2
90 4
85 6
80 8
75 10
70 12

If C0 = concentration of 100mg/mL at t=0 And C
= concentration of 90 mg/mL at t=4hr
Then: 90 = k04+100
K0 = 2.5 mg/mL hr

Careful examination of the data will also show that
the concentration of drug declines 5 mg/mL for each
2-hour interval.
Therefore, the zero-order rate constant may be
obtained by dividing 5mg/mL by 2 hours:

Applications of zero-order processes include;
Administration of a drug as an IV infusion,
Formulation and administration of a drug through
controlled release DFs and
Administration of drugs through transdermal drug
delivery systems.

Amount of drug A is decreasing at a rate that is
proportional to the amount of drug A remaining
dA/dt = -KA;
dC/dt = -kC
K
first-order rate constant; units of time–1
(eg, hr–1
)
Integration
lnA = lnAo -Kt; log A = logAo- (Kt/2.3)
lnC = lnCo – kt; log C = log Co - (Kt/2.3)
Most kinetic processes in the body follow 1st
- order
First-order kinetics

A graph of log A versus t
 Straight line
 Y-intercept = log A0
First order t1/2
t1/2 = 0.693/k
 Constant, independent of AO
First-order kinetics

1. A solution of a drug was freshly prepared at a concentration of
300mg/mL. After 30 days at 25°C, the drug concentration in the
solution was 75 mg/mL.
A. Assuming first-order kinetics, when will the drug decline to one-
half of the original concentration?
Solution: -K = 2.303 (logy2-logy1)/x2-x1 = 2.303(log75-log300)/30day-0day
-K = 2.303(log75/300)/30day = 2.303 (-0.602)/30day = -1.386/30day
K= 0.046/day
t1/2 = 0.693/K = 0.693/0.046/day = 15.065day
Examples

2. Assuming zero-order kinetics, when will the drug decline to one-
half of the original concentration?
Solution: A =-Kt+A0
75mg/ml = -K30day+300mg/ml
75mg/ml-300mg/ml = -K30day
-225mg/ml/30day = -K30day/30day =
K = 7.5mg/ml day
t1/2 = 0.5A0/K = 0.5*300mg/ml/7.5mg/ml day
t1/2 = 150day/7.5
t1/2 = 20day
Examples…

3. Assume first-order kinetics, how many half-lives (t1/2) would it take
for 99.9% of any initial concentration of a drug to decompose?
Log0.3=log300-kt/2.303
log0.3-log300=-kt/2.303
log(0.3/300) = -kt/2.303
log0.001 = -kt/2.303
-3 = -kt/2.303
t99.9% = (6.909/0.693)t1/2 = 9.97t1/2
Examples…

First-order elimination is extremely important in
pharmacokinetics
Since the majority of therapeutic drugs are
eliminated by this process.
Applications of first order process

First Order kinetics
[drug] decreases exponentially
w/ time
Rate is proportional to [drug]
Plot of log [drug] or ln[drug] vs.
time are linear
t1/2 is constant regardless of
[drug]
Zero Order kinetics
[drug] decreases linearly with
time
Rate is constant
Rate is independent of [drug]
Plot of [drug] vs. time is
linear
t 1/2 is not constant, depends
on [drug]

The handling of a drug by the body can be very
complex
Several processes (ADME) work to alter [drug] in
tissues and fluids
ADME often happen simultaneously
Simplifications of body processes are necessary to
predict a drug's behavior in the body
Pharmacokinetic models are used

PK Models
Mimic closely the physiologic processes in the body
But seldom consider all the rate processes in the body
Hypothesis using mathematical terms to describe the
quantitative r/p b/n drug concentration & time so as to
estimate PK parameters of the drug
Simplified mathematical expressions

• PK models are used to:
Predict plasma, tissue, and urine drug levels with any
dosage regimen
Calculate the optimum dosage regimen for each Pt
Estimate the possible accumulation of drugs and/or
metabolites
Correlate drug concentrations with pharmacologic or
toxicologic activity
Evaluate differences in the rate or extent of availability
between formulations (bioequivalence)
Describe how changes in physiology or disease affect the
absorption, distribution, or elimination of the drug
Explain drug interactions

Two types of PK models
Compartmental models
Physiologic models /perfusion models

Compartment
An entity which can be described by a definite volume
& concentration
Simulation of group of tissues/organs which have
similar perfusion and drug affinity
It is not a real anatomic region of the body
Body parts are grouped as highly perfused, poorly
perfused and negligible perfusion to form one or more
compartments

A. Highly perfused tissue group
 There is high blood flow to these tissues
 Lung, brain, Heart, liver, kidney, endocrine glands
 Drug concentration rapidly equilibrates with blood
B. Poorly perfused tissue group
 Poor blood flow to the tissues.
 Muscle, skin, fatty tissue, bone marrow
C. Negligible perfusion tissue group
 Negligible blood supply to the tissues
 Bone, nail, hair, ligaments, tendons, cartilages, teeth

Assumptions and Simplifications
Body is series of compartments joined reversibly together
Drug moves to- and from- each compartment
Drug is administered to the central compartment (CC)
Elimination is from the CC

Distribution of drug in a compartment is rapid and uniform
Each drug molecules in a compartment has equal
probability of leaving the compartment at any time
All rate processes follow first order kinetics
Amount of drug in the body is the sum of the amount
of drug in each compartment

Two types of compartmental models
Catenary model
Mammilary model

Compartments are joined together like compartments of a train.
The drug cannot go to 3rd
compartment without going to the 2nd
compartment.
It doesn’t apply to the way most organs are connected to the
plasma
It is rarely used (no universal acceptance)

It is the most commonly used PK model
Each peripheral compartments (PC) is
independently and reversibly connected to the CC
Like the connection between plasma and other
body organs
CC……..Plasma and highly perfused organs

 Drug is introduced to the CC and then goes to the PC
 No, one or more PCs
One compartment open model, multicompartment
open model
 Open the drug can enter and leave the compartment

Simplest compartmental model
The body is considered as a single
well-mixed container
The drug distributes instantly b/n
blood and other body
tissues/fluids
Equilibrium (steady state) is
reached rapidly

Drug is both added to and eliminated from a CC
Elimination of drug occurs from the CC because the
organs involved in drug elimination, primarily kidney
and liver, are well-perfused tissues

• Assumptions of this model
– The drug can enter or leave the body (i.e., the model is
"open")
– The body acts like a single, uniform compartment (like tank)
– Equilibrium between drug concentrations in different tissues
or organs is obtained rapidly (virtually instantaneously),
following drug input.
– Therefore, a distinction between distribution and
elimination phases is not possible.

• Assumptions of this model…
– This route of administration ensures that the entire
administered dose reaches the general circulation
– Drug elimination also occurs from the compartment
immediately after injection
– First-order process and passive diffusion are operative
– Following equilibrium, changes in drug concentration in blood
(which can be sampled) reflect changes in concentration of
drug in other tissues (which cannot be sampled).

Compartmental models
Simple and flexible
Limited amount of data to
determine PK parameters
Empirical/ lacking physiologic
relevance
Don’t consider pathophysiologic
changes
Plama conc. vs time
PK parameters
Physiologic models
Complicated
Large amount of data
required
Real physiology and anatomy
Can evaluate effect of
pathophysiologic changes
Drug distribution
Uptake & clearance by organs

1. Introduction and Basic PK (1).ppt and

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