Relationship between Pharmacokinetics and

Pharmacodynamics

 As defined by F.H. Dost in 1953, Pharmacokinetics is a

science dealing with study of biological fate of drug &/or its
metabolite(s) during its sojourn within the body of a man or
animal, with the help of mathematical modeling.

 In simple words it is the study of what body does to the drug.

 The term Pharmacokinetics was coined by Torston Teorell.

 It involves the study of ADME.

 SCHEMATIC REPRESENTATION ADME

DOSE

ABSORPTION

DRUG IN
DISTRIBUTION DRUG IN
SYSTEMIC
TISSUES
CIRCULATION

ELIMINATION

EXCRETION
AND
METABOLISM

 It refers to the relationship between drug concentration at the

site of action and the resulting effect, including the time
course and intensity of therapeutic and adverse effects.

 In simple words it is the study of what drug does to the body.

 IUPAC definition : Branch of pharmacology concerned with

pharmacological actions on living systems, including
reactions with and binding to cell constituents, and the
biochemical and physiological consequences of these
actions.
 RECEPTOR OCCUPANCY MODEL

 Given by Langley, hill and Clarke.

 Based on law of Mass Action.

 Drug effect is related to proportion of receptors occupied.

K1
[DRUG] + [RECEPTOR] [DRUG][RECEPTOR]
K2

RESPONSE

 Any drug that binds to a receptor and stimulates the

functional activities
 Has both affinity as well as intrinsic activity.
 e.g. Ach

Receptor
Some Effect

Acetylcholine

A Cell
 It has affinity to receptor but no intrinsic activity.
 It prevents binding of agonist to receptor.
 e.g. atropine

Atropine

Dude, you’re
in my way!

Acetylcholine

 Any drug that binds to a receptor and produces an

opposite effect as that of an agonist.

Receptor
Effect opposite
to that of
the true agonist

Inverse agonist

A Cell
 Produces a sub maximal response.
 Affinity is there but intrinsic activity is less than agonist.

Submaximal
Partial agonist
effect

Oh!!!, I should
Have been here

True agonist

 RATE THEORY
 Pharmacological response is not dependent on drug-receptor
complex concentration but rather depends upon rate of
association of drug and receptor.

 LOCK AND KEY MODEL

 Only a drug of specific chemical structure can bind with the
receptor.

 INDUCED FIT MODEL

 When the drug binds to the receptor, it produces some
conformational change in the receptor which helps in better
fitting of the drug inside active site of receptor.
Revision

One compartment PK model:

-Denoted by a closed box

-Assumes the body is

composed of a single
homogenous compartment

-The drugs distributes equally

and uniformly to all the body
Revision

Two compartment PK model:

-Denoted by two closed boxes

-Assumes the body is

composed of a two
compartments
-Central ( highly perfused)
-Peripheral (poorly
perfused)

-The drug is usually eliminated

from the central compartment

Revision Three compartment PK model:

-Denoted by two closed boxes

-Assumes the body is

composed of a three compartments
-Central ( highly perfused)
-Tissue compartment
-Deep tissue compartment
-The drug is usually eliminated
from the central compartment
 Revision

Route of
Dose Cp Zero order
administration
Amount of drug
Elimination eliminated per unit
rate time is constant
constant
First order

Amount of drug
eliminated per unit time
is proportional to the
drug remaining

RELATION OF DOSE TO PHARMACOLOGIC EFFECT

The onset, intensity, and duration of the pharmacologic effect depend
on the dose and the pharmacokinetics of the drug. As the dose
increases, the drug concentration at the receptor site increases, and the
pharmacologic response (effect) increases up to a maximum effect. A
plot of the pharmacologic effect to dose on a linear scale generally
results in a hyperbolic curve with maximum effect at the plateau (). The
same data may be compressed and plotted on a log-linear scale and
results in a sigmoid curve ().

Plot of pharmacologic response versus dose on a linear scale.

Typical log dose versus pharmacologic response curve.

For many drugs, the graph of log dose–response curve shows a linear relationship at a
dose range between 20-80% of max response , which is therpeutic dose range for many
drugs.
For a drug that follows one-compartment pharmacokinetics, the volume of distribution
is constant; therefore, the pharmacologic response is also proportional to the log
plasma drug concentration within a therapeutic range as shown in

Graph of log drug concentration versus pharmacologic effect. Only the linear portion of the curve is shown.
Mathematically, the relationship in may be expressed by the following equation, where
m is the slope, e is an extrapolated intercept, and E is the drug effect at drug
concentration C:

Solving for log C yields

However, after an intravenous dose, the concentration of a drug in the body in a

one-compartment open model is described as follows:

By substituting Equation 19.2 into Equation 19.3, we get Equation 19.4, where E 0 = effect at
concentration C

0:

The theoretical pharmacologic response at any time after an intravenous dose of a

drug may be calculated using Equation 19.4. Equation 19.4 predicts that the
pharmacologic effect will decline linearly with time for a drug that follows a one-
compartment model, with a linear log dose–pharmacologic response. From this
equation, the pharmacologic effect declines with a slope of km/2.3. The decrease in
pharmacologic effect is affected by both the elimination constant k and the slope m.
For a drug with a large m, the pharmacologic response declines rapidly and multiple
doses must be given at short intervals to maintain the pharmacologic effect.
RELATIONSHIP BETWEEN DOSE AND DURATION OF ACTIVITY (teff),
SINGLE IV BOLUS INJECTION
The relationship between the duration of the pharmacologic effect and the dose can be inferred from
Equation 19.3. After an intravenous dose, assuming a one-compartment model, the time needed for
any drug to decline to a concentration C is given by the following equation, assuming the drug takes
effect immediately:

Using C eff to represent the minimum effective drug concentration, the duration of drug action
can be obtained as follows:

Some practical applications are suggested by this equation. For

example, a doubling of the dose will not result
in a doubling of the effective duration of pharmacologic
action. On the other hand, a doubling of t 1/2 or a corresponding
decrease in k will result in a proportional increase in duration of
action. A clinical situation is often encountered in the treatment of
infections in which C eff is the bacteriocidal concentration of the drug,
and, in order to double the duration of the antibiotic, a considerably
greater increase than simply doubling the dose is necessary.
Practice Problem
The minimum effective concentration (MEC) in plasma for a certain antibiotic is 0.1
u g/mL. The drug follows a one-compartment open model and has an apparent volume
of distribution, V D, of 10 L and a first-order elimination rate constant of 1.0 hr- 1.
a. What is the t eff for a single 100-mg IV dose of this antibiotic?
b. What is the new t eff or t'eff for this drug if the dose were increased 10-fold, to 1000
mg?
Solution
a. The t eff for a 100-mg dose is calculated as follows. Because V D =
10,000 mL,

For a one-compartment-model IV dose, C = C 0 e - kt.

Then

b. The t'eff for a 1000-mg dose is calculated as follows (prime refers to a new dose). Because V D =
10,000 ml

and

The percent increase in t eff is therefore found as

This example shows that a 10-fold increase in the dose increases the duration of action of a drug (t
eff ) by only 50%
EFFECT OF BOTH DOSE AND ELIMINATION HALF-LIFE ON THE
DURATION OF ACTIVITY
A single equation can be derived to describe the relationship of dose (D 0) and the
elimination half-life (t 1/2) on the effective time for therapeutic activity (t eff ). This
expression is derived below.

Because C 0 = D 0 /V D,

Substituting 0.693/t 1/2 for k,

From Equation 19.8, an increase in t 1/2 will increase the t eff in direct proportion.
However, an increase in the dose, D 0, does not increase the t eff in direct
proportion. The effect of an increase in V D or C eff can be seen by using generated
data. Only the positive solutions for Equation 19.8 are valid, although mathematically a
negative t eff can be obtained by increasing C eff or V D. The effect of changing dose on t
eff is shown in using data generated with Equation 19.8. A nonlinear increase in t eff is
observed as dose increases.
Table 19.1 Relationship between Elimination Half-Life and Duration of Activity

Dose (mg/kg) t 1/2 = 0.75 hr t eff (hr) t 1/2 = 1.5 hr t eff (hr)

2.0 3.24 6.48

3.0 3.67 7.35
4.0 3.98 7.97
5.0 4.22 8.45
6.0 4.42 8.84
7.0 4.59 9.18
8.0 4.73 9.47
9.0 4.86 9.72
10 4.97 9.95
11 5.08 10.2
12 5.17 10.3
13 5.26 10.5
14 5.34 10.7
15 5.41 10.8
16 5.48 11.0
17 5.55 11.1
18 5.61 11.2
19 5.67 11.3
20 5.72 11.4
 PK/PD modeling is a scientific mathematical tool which
integrates PK model to that of PD model.
 PK model - describes the time course of drug concentration
in the plasma or blood.
 PD model - describes the relationship between drug
concentration at site of action and effect.
 PK/PD models use data derived from plasma drug
concentration vs. time profile and from the time course of
pharmacological effect to predict the Pharmacodynamics of
the drug.
 Result is summation of Pharmacodynamics and
pharmacokinetics effect.

Simple direct effect Nonsteady-state & time-

models dependent models

Biophase
Linear model distribution
model

Signal
Log-linear transduction
model
model

Tolerance
Emax model model

Mechanism
Sigmoidal Emax based indirect
model
response model
Effect of drug is direct.

Fast mechanism of action.

Rapid equilibrium exists Linear Log-Linear

model Model
between site of action and
the sampling biofluids.

PD parameters are time Sigmoidal

Emax Model
Emax Model
invariant.

 Drug effect is directly proportional to drug concentration.

 Pharmacodynamically it is explained as:
E∝ C …..(1)
E = Sî C …..(2)
where,
E = Effect of drug
C = Drug concentration
S = Slope obtained from E vs C graph
 In case of baseline effect (E0), when the drug is absent, model
may be represented as:
E = E0 + S*C …..(3)
 E = E0 + S*C
S
y = c + mx
Effect

so,
E0 slope = S
intercept= E0
Concentration

Advantages
 Model is simple and parameter estimation can be easily
performed by linear regression.

Limitations
 Applicable at low drug concentrations only
 excludes the prediction of maximum effect

Example
 Relationship between central activity of diazepam and
plasma drug concentration
 When the effect of drug is measured over a large range, the
relationship between concentration and effect is not linear
and may be curvilinear and log transformation is needed.
 The log concentration-Effect is roughly linear in
concentration range of 20-80% of maximum Effect.
 It is given by:
E = E0 + S*log C …(4)
where,
E = effect
E0=Baseline effect
S = slope
C= concentration

Log C
 It expands the initial part of the curve where response is
slowly making progression before it accelerates
 It contracts the latter part of the curve where a large change
in concentration produces a slight change in response.
 In middle part relationship is linear.
 Advantage
 Unlike linear model it is applicable over large concentration
range.

Limitations
 Pharmacological effect cannot be estimated when the
concentration is zero because of the logarithmic function.
 Maximum effect cannot be predicted.

Example
 This model has been successfully used in predicting the
pharmacological activities of beta blockers and
anticoagulants.

 This model incorporates the observation known as the law

of diminishing returns.
 This law shows that an increase in drug concentration near
the maximum pharmacological response produces a
disproportionately smaller increase in the pharmacological
response.
 This model describes the drug action in the terms of :
 E max (maximum effect)
 EC50 ( the drug concentration that produces 50%
maximum pharmacological effect)

Em axC ….(5)
E
EC50  C
 It mimics the hyperbolic shape of pharmacologic response
vs. drug concentration curve.
 After maximum response (Emax) has reached, no further
increase in pharmacologic response is seen on increase in
concentration of the drug.
 EC50 is useful for determining drug concentration that lies
within the therapeutic range.

Emax

E
EC50

Contd…
In case, there is a baseline effect i.e. the measured
pharmacologic effect has some value in absence of drug (e.g.
blood pressure, heart rate, respiratory rate) then the equation
becomes:
Em axC
E  Eo
EC 50  C ….(6)

where,
E0 = Pharmacologic effect (baseline activity) at zero
drug concentration in the body

It is a saturable process and resembles the Michaelis-Menton

equation.
 Contd…
 A double-reciprocal plot of equation is used to linearize the
relation, similar to Lineweaver-Burke equation.

1 EC50 1
 
E E m axC E m ax …(7)

1/E slope = EC50 / Emax

1/ Emax

-1/ EC50 1/C

Advantages
 Maximum pharmacological response can be found out.
 EC50 can be calculated (i.e., concentration needed to
produce half maximum response).
Limitations
 In case of highly potent drugs it is not possible to find the
maximum effect because test organisms die long before the
maximum effect is attained.
 The method can be time consuming if maximum effect is
obtained at a very high concentration.
Example
 Bronchodilator activity of Theophylline is studied by this
model.
 Given by Hill.
 It describes the pharmacologic response versus drug
concentration curve for many drugs that appear to be S-
shaped (i.e. Sigmoidal) rather than hyperbolic as
described by more simple Emax model.
 The equation for the sigmoid Emax Model is an extension
of the Emax Model:
E max C n
E 
EC 50  C n …(8)
n is an exponent describing the number of drug molecules
that combine with each receptor molecule.
When n=1, the Sigmoid Emax Model reduces to the Emax Model

 A value of n>1 influences the slope of the curve and the

model fit.

 In the Sigmoid Emax Model, the slope is influenced by the

number of drug molecules bound to the receptor.

 A very large n value may indicate allosteric or cooperative

effects in the interaction of the drug molecules with the
receptor.

 Cooperativity is the case when binding of substrate at on

binding site affects the affinity of other sites to their
substrates.
 Graphical representation

n>1

EMAX n=1

E E n<1
EC50

CONCENTRATION CONCENTRATION

Biophase
distribution model

Mechanism-based
indirect response
model
Signal
transduction
model

Tolerance model
 Indirect effect of the drug.

 The effect is not immediate.

 Distribution of the drug is the rate limiting step.

 Slow association and dissociation of drug with the

receptors.

 For some drugs, the pharmacologic response produced by

the drug may be observed before or after the plasma drug
concentration has peaked. Such drugs may produce
indirect or delayed response.

 Drug distribution to the effect site may represent a rate-

limiting step for drugs in exerting their pharmacological
effect.

 To account for this indirect or delayed response, a

hypothetical effect compartment has been postulated by
Holford and Sheiner.
 EFFECT COMPARTMENT
It is not part of the pharmacokinetic model but is a
hypothetical pharmacodynamic compartment that links to the
plasma compartment containing drug.

It is because amount of drug entering this compartment is

considered to be negligible and is therefore not reflected in
pharmacokinetics of the drug.

k1e keo
V C1 Ve Ce Effect

k1

Plasma Effect
Compartment Compartment
Drug transfer from plasma to hypothetical effect compartment
takes place with first order rate constant.

Only free drug can diffuse into the effect compartment.

The pharmacological response of the drug depends on the rate

constant ke0 and the drug concentration in the effect
compartment.
The amount of drug in the effect compartment after i.v. bolus
dose may be given by:
dDe  k 1eD1  ke0 De ...(9)
dt
where,
De = amount of drug in effect compartment
D1 = amount of drug in central compartment
ke0 = rate constant for drug transfer out of the effect
compartment
K1e = rate constant for drug transfer from plasma to effect
compartment

Integrating the equation we get:

D0 k1e
De  (e kt  e ke 0t ) …(10)
(ke 0  k )
Dividing by Ve ,

D0 k1e …(11)
Ce  (ekt  e ke 0t )
Ve (ke 0  k )

The above equation is not very useful as parameters Ve and

k1e are both unknown and cannot be obtained from plasma
drug concentrations. Therefore assumptions are made.
 Assumptions
 Even though an effect compartment is present in addition
to the plasma compartment, this hypothetical effect
compartment takes up only a negligible amount of the
drug dose.
 So plasma drug level still follows a one-compartment
equation.
 After an IV bolus dose, the rate of drug entering and
leaving the effect compartment is controlled by k1e and
ke0.
 At steady state,
input = output
k1eD1 = keoDe …(12)
Rearranging,
k D
D 1  e0 e …(13)
k1e
Dividing by VD yields the steady state plasma drug concentration
C1
k e0 De
C 1 …(14)
k 1eV D
D0 k1e
De  (e  kt  e  ke 0t )
(ke 0  k ) from eq.…(10)
substituting De in equation (14)

ke 0 D0 k1e
C1  (e kt  e ke 0t ) …(16)
k1eVD (ke 0  k)

ke 0 D0 k
C1  (e kt  eke 0t ) …(17)
VD (ke0  k )

 At steady state, C1 is unaffected by k1e but depends on

k and ke0.

 C1 is the steady state concentration and has been used

to relate the pharmacokinetic effect of many drugs,
including some of delayed equilibrium between plasma
and effect compartment.

 k and ke0 jointly determine the pharmacodynamic

profile of the drug.
 Dynamic flexibility and adaptability.

 The model accommodates the aggregate effects of drug

elimination, binding, partitioning and distribution.

 Model represent in vivo pharmacologic event relating to

plasma drug concentration that clinician can monitor and
adjust.

This model has been used to characterize the PK/PD of several

drugs (e.g. midazolam, pancuronium, alprazolam, etc.) whose
plasma concentrations could not be correlated with the effect
being produced.

The indirect response model is based on the premise that the

drug response is indirectly mediated by either inhibition or
stimulation of the factors controlling either the production
(Kin) or the dissipation of response (Kout).

EXAMPLES:
 Indirect response modeling was first introduced by
Nagashima et al. for the anticoagulant effect of warfarin.

 These models may be appropriate for various classes of

drugs, including histamine H2-receptor antagonists (such
as cimetidine) and oral hypoglycemic agents (such as
tolbutamide).
 Kin Kout
Response

Stimulation Stimulation
Or Or
Inhibition Inhibition

[DRUG] [DRUG]

In the absence of drug, the rate of change in response over

time (dR/dt) can be described by a differential equation as
follows:

dR
 k in  k out R …(18)
dt
where,
R = response
kin = zero-order rate constant for the production of
response
kout = first order rate constant for the dissipation of
response

Used in cases where endogenous mediators are involved in

the expression of the response.
 SIGNAL TRANSDUCTION MODEL

The pharmacological effects

of drugs may be mediated by a
time-dependent signal
transduction process, in
which the response measured
clinically involves multiple
steps removed from the initial
biochemical effect of the drug.

CONTD…
 There are two major classes of receptors involved in signal
transduction process:
1.cell membrane receptors
2.cytosolic/nuclear receptors

 Since cascade of steps is involved in signal transduction,

theoretically there should be delay between each step.
 Owing to technical and research limitations at cellular and
molecular level, PD response vs. time relationship for every
step is difficult to obtain.
 To characterize such delayed effects stochastic models with
transit compartments and transit times are employed.
 This model has been used to characterize the
parasympathomimetic activity of scopolamine and atropine
in rats.
 D+R DR

τ τ τ
1 2 3 N

TOLERANCE MODEL

 Tolerance is characterized by a reduction in pharmacological

response after repeated or continuous drug exposure.

 For some drugs, pharmacodynamic parameters like Emax and

EC50 may appear to vary over time, resulting in changes in
pharmacological response despite the presence of constant
concentrations at the effect site.

 The complex mechanism of tolerance may involve:

receptor pool depletion
decrease in receptor affinity
 The development of tolerance can have a significant impact
on the exposure-response relationship and, if not
recognized, can contribute to poor clinical outcome.

 Pharmacokinetic/ pharmacodynamic modeling can be a

very useful tool to characterize the time course and
magnitude of tolerance development.

53

EXAMPLES

An increase in EC50 over time for Terbutaline which is

likely attributed to a decrease in the receptor number’

Development of tolerance to the acid inhibitory effect of

ranitidine. The derived model indicated that ranitidine
developed tolerance with increased EC50 by 100% within 6 –
10 hr after prolonged IV administration.

54
 Many pharmacological responses are complex and do not
show a direct relationship between pharmacologic effect
and plasma drug concentration.

 Some drugs have a plasma drug concentration and response

that resembles hysteresis loop.

 Hysteresis is defined as ‘the retardation or lagging of an

effect behind the cause of the effect’.

 An alternative definition would be ‘failure of one of two

related phenomena to keep pace with the other’.

Identical drug concentration can result in different

pharmacological response, depending on whether the plasma
drug concentration is on ascending or descending phase of the
loop.

Hysteresis

Clockwise Anticlockwise
 Here response decreases with time.

E2

E
E1

C1
C

 If we take a concentration say (C1), it can be clearly seen

that the response at this concentration decreases from E2 to
E1 with passage of time

1.Fentanyl and Alfentanil

Explanation: These are opioid analgesics and have
high lipid solubility. Initially, with increase in plasma
concentration effect is increasing proportionally but
after some times effect decreases due to redistribution
of drug.

2.Isoprterenol
Explanation: The diminished response is due to result
of cellular response and physiologic adaptation to
intense stimulation of drug.

3.Acetazolamide
Explanation: physical adaptation.
 4.Amphetamine
Explanation: Exhaustion of mediators.

 5. Anticonvulsants
Explanation: Increased metabolism.

 6.
Benzodiazepenes
Explanation: Loss of modulator binding site.

 In the counterclockwise hysteresis loop, response increases

with time.

E2

E1

C1
C
 If we take a concentration say (C1), it can be clearly seen
that the response at this concentration increases from E1to
E2 with passage of time.
1.Ajmaline
Explanation: Drug is highly bound to α1-AGP and
initial diffusion of drug into effect compartment is
slow.

2.Pancuronium
Explanation: Slow movement of ionized compound
from capillaries to NMJ.

3. Morphine
Explanation: Slow entry into CNS due to low lipid
solubility .

APPLICATIONS
OF PK/PD
MODELING
1.PK/PD STUDIES IN DRUG DEVELOPMENT

• Pharmacokinetic (PK) and pharmacodynamic (PD) modelling

and simulation (M&S) are well-recognized powerful tools
that enable effective implementation of the learn-and confirm
paradigm in drug development.

• M&S methodologies can be used to capture uncertainty and

use the expected variability in PK/PD data generated in
preclinical species for projection of the plausible range of
clinical dose.
Clinical trial simulation can be used to forecast the
probability of achieving a target response in patients
based on information obtained in early phases of
development.

1–3 years 2–10 years 1–2 years

Discovery, Clinical Research and

Preclinical Testing, Development
Research and 20–80 healthy volunteers
Development
Phase I
First in human, PK, tolerability Postmarketing
NDA Surveillance
50–100 patients
Initial synthesis of
compounds Phase II
Review
Evidence of effectiveness, safety
Animal testing
1000–3000 patients
Phase III
Short-term Verify effectiveness, long-term
safety safety and adverse reactions
Long-term safety

IND submitted to FDA NDA submitted to FDA

30-day safety review 10–12 months review
FIGURE 21-1 New drug development process. (Adapted from Peck et al, 1994.)
 PK/PDMODELING
3.PK/PD STUDIES IN
INDOSAGE REGIMEN
INTERSPECIES
OPTIMISATION:
EXTRAPOLATION:

 Primary source of between-species variability is often

attributable
PK/PD to variability
modeling that istool
is a scientific mainly of developers
to help PK origin.
select a rational dosage regimen for confirmatory clinical
testing.
 Drug plasma concentration required to elicit a given
Applied
responsetoisindividual dosebetween
rather similar optimization.
species, whereas the
corresponding dose for eliciting the same effect can differ
Time course and variability in the effect versus time
widely.
relationship can be predicted for different dosage-regimen
scenarios.

3.PK/PD MODELING IN INTERSPECIES

EXTRAPOLATION:

 Primary source of between-species variability is often

attributable to variability that is mainly of PK origin.

 Drug plasma concentration required to elicit a given

response is rather similar between species, whereas the
corresponding dose for eliciting the same effect can differ
widely.
 4. EXTRAPOLATION FROM in vitro to in vivo:
If an efficacious concentration (EC for stimulation, IC for
inhibition) is obtained on the basis of an in vitro assay, then
a dose can be proposed by incorporating the in vitro EC
directly into equation:

ED 50 = Cl x EC 50/Bioavailability

As in vitro concentrations are generally equivalent to free

drug concentrations, corrections for drug binding to plasma
protein might be needed to estimate the corresponding in-
vivo plasma
EC or IC.

5. APPLICATIONS OF PK/PD METHODS

STUDY DRUG INTERACTIONS:

Drug interactions study protocols often incorporate

pharmacodynamic endpoints to allow estimating the clinical
consequences of drug interactions along with the usual
pharmacokinetic outcome measures.

Example:
Co-administration of triazolam and erythromycin produced a
large increase in plasma concentration of triazolam.
Thank you