PKPD Modelling
PKPD Modelling
PKPD Modelling
PHARMACODYNAMIC
MODELING
PRESENTED BY
Jaspreet Singh
Deepika
(M.Pharm I)
PHARMACOKINETICS
DRUG IN
TISSUES
PHARMACODYNAMICS
K1
[DRUG][RECEPTOR]
K2
RESPONSE
Receptor
Some Effect
Acetylcholine
A Cell
Atropine
Dude, youre
in my way!
Acetylcholine
Receptor
Effect opposite
to that of
the true agonist
Inverse agonist
A Cell
Partial agonist
Oh!!!, I should
Have been here
True agonist
Submaximal
effect
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.
SIMPLE DIRECT
EFFECT/STEADYSTATE/TIME
INVARIANT MODELS
ADVANCED/NON
STEADY-STATE/TIME
DEPENDENT MODELS
Linear model
Biophase
distribution
model
Log-linear
model
Signal
transduction
model
Emax model
Tolerance
model
Sigmoidal Emax
model
Mechanism
based indirect
response model
Sigmoidal
Emax Model
Linear
model
Log-Linear
Model
Emax Model
LINEAR MODEL
GRAPHICAL REPRESENTATION
Effect
E0
Concentration
E = E0 + S*C
y = c + mx
so,
slope = S
intercept= E0
Contd
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
LOG-LINEAR MODEL
GRAPHICAL REPRESENTATION
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.
Contd
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.
Emax.(5)
C
E
EC50 C
Contd
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:
Emax C
E Eo
.(6)
EC50 C
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
EC50
1
1
E Emax(7)
C Emax
1/E
1/ Emax
-1/ EC50
1/C
Contd
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.
SIGMOIDAL E MODEL
max
Given by Hill.
It describes the pharmacologic response versus drug
concentration curve for many drugs that appear to be Sshaped (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:
Emax C n
E
EC50 C n
(8)
Contd
Graphical representation
n>1
EMAX
n=1
n<1
EC50
CONCENTRATION
CONCENTRATION
BASIC CHARACTERS
Drug distribution to the effect site may represent a ratelimiting step for drugs in exerting their pharmacological
effect.
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.
V C1
k1e
Ve Ce
keo
Effect
k1
Plasma
Compartment
Effect
Compartment
Contd
The amount of drug in the effect compartment after i.v. bolus
dose may be given by:
dDe k 1eD1 ke 0 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
Contd
Integrating the equation we get:
(10)
D0 k1e
De
(e kt e ke 0t )
(ke 0 k )
Dividing by Ve ,
Ce
D0 k1e
(e kt e ke 0t )
Ve (k e 0 k )
(11)
Assumptions
k e 0 D(13)
e
D1
k1e
(12)
k e 0 De
C1
k1eVD (14)
D0 k1e
De
(e kt e ke 0t )
(ke 0 k )
from eq.(10)
substituting De in equation (14)
C1
C1
ke 0 D0 k1e
(e kt (16)
e k e 0t )
k1eVD (ke 0 k )
ke 0 D0 k
VD (ke 0 k )
(e kt e ke 0t )
(17)
Contd
ADVANTAGES
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.
Kin
Stimulation
Or
Inhibition
[DRUG]
Response
Kout
Stimulation
Or
Inhibition
[DRUG]
MATHEMATICAL REPRESENTATION
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
kin kout R
dt
(18)
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.
dR
Kin I t Kout R
dt
dR
Kin Kout I t R
dt
(Stimulation of production)
dR
Kin S t Kout R
dt
dR
Kin Kout S t R
dt
(Dissipation of response)
EXAMPLES
1. H2-receptor antagonist: Inhibition of gastric secretion.
which MODEL is it
representing?
Model I
Contd
2. Induction of MX protein synthesis: Interferon -2a
Now which
model is it?
MODEL III
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
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
CONTD
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
Hysteresis
Clockwise
Anticlockwise
CLOCKWISE HYSTERESIS
E2
E
E1
C1
C
EXAMPLES
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.
CONTD
4.Amphetamine
Explanation: Exhaustion of mediators.
5. Anticonvulsants
Explanation: Increased metabolism.
6. Benzodiazepenes
Explanation: Loss of modulator binding site.
C1
C
EXAMPLES
1.Ajmaline
Explanation: Drug is highly bound to 1-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 .
2.
3.
CONTD.
ADVANTAGE :
Simplicity
LIMITATIONS :
Requires extensive sampling for each individual in order to
estimate individual parameters.
It has been shown from simulation studies that the standard
two stage approach tends to overestimate parameter
dispersion.
65
LIMITATIONS
Contd
Analyzes the data of all individuals at once, estimating
individual and population parameters, as well as the
interindividual, intraindividual residual, and interoccasion
variabilities.
It also allows the evaluation and quantification of potential
sources of variability in pharmacokinetics and
pharmacodynamics in the target population.
Influence of patient demographics (e.g., weight, gender,
age, etc.) and pathophysiological factors (e.g., hepatic
function, renal function, disease status, etc.) on drug PK
and PD disposition may be assessed.
Contd
Useful in the design of dosing regimens and
therapeutic drug monitoring.
The non-linear mixed-effects model is the most
widely used method and has proven to be very useful
for continuous measures of drug effect, categorical
response data, and survival-type data.
BIOMARKERS
Detection of biomarker
Quantitative
a link between quantity of the marker and disease .
Qualitative
a link between existence of a marker and disease.
An Ideal Marker should have great sensitivity, specificity, and
accuracy in reflecting total disease burden. A tumor marker
should also be prognostic of outcome and treatment
CLASSIFICATION OF BIOMARKERS
ANTECEDENT BIOMARKERS : Identifying the risk of
developing an illness. e.g. amyloidal plaques start forming
before the symptoms of AD appear.
SCREENING BIOMARKERS: Screening for subclinical
disease. E.g. abnormal lipid profile is a screening marker of
heart disease.
DIAGNOSTIC BIOMARKERS: Recognizing overt
disease. E.g. Diagnostic kits for various diseases.
STAGING BIOMARKERS : Categorizing disease
severity.
PROGNOSTIC BIOMARKERS: Predicting future
disease course, including recurrence and response to
therapy and monitoring efficacy of therapy.
APPLICATIONS OF BIOMARKERS
Use in early-phase clinical trials to establish proof of
concept.
Diagnostic tools for identifying patients with a specific
disease.
As tools for characterizing or staging disease processes.
As an indicator of disease progress.
For predicting and monitoring the clinical response to
therapeutic intervention.
APPLICATIONS
OF PK/PD
MODELING
Contd
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.
Contd
LEARN AND CONFIRM DRUG-DEVELOPMENT
PARADIGM
Contd
PRECLINICAL PHASE:
OVERALL OBJECTIVE:
Contd
Contd
Combination of M&S approaches, including population analysis
of sparse preclinical PK data, allometric scaling to predict human
PK, and empirical efficacy scaling, can be used to project the
anticipated human dose and/or dosing regimen.
This can be explained by a case study:
Contd
Contd
The concentration-response parameters for the NCE in clinical
hypertension were calculated using an empirical scaling
approach by combining the results of the rat hypertension Emax
model parameters and the clinical Emax model parameters of the
comparator.
Contd
Phase 1 starts with dose escalating studies in normal
volunteers with rigorous sampling. In addition, one may
establish an initial doseconcentrationeffect relationship
that offers the opportunity to predict and assess drug
tolerance and safety in early clinical development.
Quantitative doseconcentrationeffect relationships
generated from PK/PD modeling in Phase1 can be utilized in
Phase 2 study design.
PK/PD modeling is an important tool in assessing drugdrug interaction potential.
Dosage form improvements often occur based on the PK
properties of the drug candidate.
Contd
Phase 2
Phase 2 trials are typically divided into two stages, each with
some specific objectives.
Phase 2A : is to test the efficacy hypothesis of a drug
candidate, demonstrating the proof of concept.
Phase 2B : is to develop the concentrationresponse
relationship in efficacy and safety by exploring a large
range of doses in the target patient population.
The PK/PD relationship that has evolved from the
preclinical phase up to Phase 2B is used to assist in
designing the Phase 3 trial.
Contd
PHASE 3:
OBJECTIVE:
To provide confirmatory evidence that demonstrates
an acceptable benefit/risk in a large target patient
population.
This period provides the ideal condition for final
characterization of the PK/PD in patients as well as for
explaining the sources of interindividual variability in
response, using population PK/PD approaches.
Contd
NDA REVIEW:
PK/PD modeling plays an important role during the NDA
submission and review phase by integrating information from
the preclinical and development phases.
Existence of a well defined PK/PD model furthermore
enables the reviewer to perform PK/PD simulations for various
scenarios.
This ability helps the reviewer gain a deeper understanding of
the compound and provides a quantitative basis for dose
selection.
Thus, PK/PD modeling can facilitate the NDA review
process and help resolve regulatory issues.
Contd
POST MARKETING PHASE:
Post-marketing strategy, population modeling approaches
can provide the clinician with relevant information regarding
dose individualization by:
Characterizing the variability associated with PK and
PD.
Identifying subpopulations with special needs.
Contd
EXAMPLE:
FOR DEVELOPMENT OF A NEW ANTIMICROBIAL
AGENT:
Serial concentration-time data were available from 19 healthy,
male and female subjects administered NCE in doses ranging
from
1 to 200 mg in the first single-dose-multiple-dose study in
humans.
A 2-compartmental population PK model best described the
data.
For the first efficacy trial in patients, the target concentration
was defined based on the concentration required to kill
90% of the susceptible bacterial strains, or IC90, determined
from an Emax model fit of in vitro exposure-kill data.
Contd
The clinical target concentration was 1.7 mcg (mcg)/mL
(calculated by dividing in vitro IC90, or 0.05 mcg/mL, by
plasma bound fraction of 0.03).
Given the target exposure, the population PK model, and
margin of safety based on preliminary preclinical safety the
objective of M&S for the first efficacy trial was to select one
dose level to be studied as a once-a-day regimen that would
maintain concentrations >1.7 mcg/mL for the entire dosing
period in 85% of the patients.
Contd
To minimize the risk of underpredicting the dose, a 20%
higher clearance (lower exposure) was assumed, and an
additional 10% variability was added to the between-subject
variability in
clearance and volume for patients. Concentration-time data
were simulated for 500 patients administered daily doses
ranging from 100 to 300 mg for 14 days. Eighty-five percent
of patients maintained the 24-hour trough concentrations
above the target at doses >200mg.
The 200-mg dose, therefore, met the criteria as the lowest
dose, which maintains persistent drug exposure for the entire
dosing interval in 85% of the patient population.
4. SELECTION OF ANTIBACTERIAL
AGENT:
PK/PD parameters correlate the bacteriological and clinical
outcome in animal models and in humans.
PK/PD parameters (AUC/MIC, Cmax/MIC) can be used to
select agents with maximum potential for bacterial
eradication.
WHERE IT IS USED