Piyush lodhi b. pharma 6th sem APPLICATIONS OF PHARMACOKINETICS

1. School Of Studies in Pharmaceutical Science
Jiwaji University Gwalior
474011
Assignment on - APPLICATIONS OF
PHARMACOKINETICS
SUBMITTED TO -
Mr. Ramakant Joshi Sir
SUBMITTED BY -
Piyush Lodhi
B-Pharma (6th.Sem.)

2. CONTENTS
➢INTRODUCTION TO PHARMCOKINETICS
➢DESIGN OF DOSAGE REGIMEN AND MULTIPLE
DOSING
 PHARMACOKINETICS BASED DESIGN
 LOADING AND MAINTENANCE DOSE
➢DESIGN OF CONTROLLED RELEASE
 PHARMACOKINETICS
 DRUG RELEASE PATTERNS

3. INTRODUCTION TO PHARMACOKINETICS
➢Pharmacokinetics is the study of the time course of drug absorption,
distribution, metabolism, and excretion. Italsoconcerns the relationship
of these processes to the intensity and time course of pharmacologic
(therapeuticand toxicology) effects of drugsand chemicals.
➢ Pharmacokinetics is a quantitativestudy
➢The birth of pharmacokinetics really occurred in the 1920s and 1930s,
being marked by the classical papers of HAGGARD (1924) on the
dispositionof ethyl ether, WIDMARK (1932) on ethyl alcohol elimination,
and TEORELL (1937a,b) on the mathematics associated with
pharmacokinetic modeling.
➢rapid growth in pharmacokinetics was paralleled by advances in
analytical instrumentation and technology, particularly high-pressure
liquid chromatography (HPLC) and growth in metabolism technology

4. Administration
of thedrug
collection of
biological
samples and
obtaining the
data using
analytical
procedures
Analysis of data
Model approach Model independentapproach
Statistical moment
approach
How modeling?
➢Structural
modeling
➢Parameter
estimation
✓Compartment
modeling
✓Physiological modeling
✓Distributed parameter
modeling
OVERVIEW OF PHARMACOKINETICS

5. APPLICATION OF PHARMACOKINETICS
I. Design and dvpt of drugs with lesserside effectsand
improved therapeuticeffectiveness
II. Design and dvpt of optimum formulation for betteruse
of drug
III. Design and dvpt of targeted and controlledrelease
formulation
IV. Design of multiple dosageregimen
V. Selection of appropriate route ofadministration
VI. Select of rightdrug for particular illness
VII. Predict interactions
VIII.TDM
IX. Dosageadjustments at timesof altered physiology

6. DESIGN OF DOSAGE REGIMEN AND MULTIPLE DOSING
➢Dosage regimen is the manner in which a drug is taken. It is the selection of drug
dosage, route, and frequency of administration in an informed manner to achieve
therapeuticobjectives.
➢Duration of most illness is longer than a single dose. Therefore to prolong the
therapeutic effect multiple dosing dosage regimen ispreferred.
An optimal dosage regimen is theone
in which the drug is administered in
suitable doses, with sufficient
frequency that ensures maintenance
of plasma concentration within the
therapeutic window (without
excessive fluctuation and drug
accumulation) for the entire duration
of therapy

7. DOSAGE REGIMEN
DOSE SIZE
DOSE
FREQUENCY
APPROACHES TO DESIGN OF DOSAGE REGIMEN
❑Empirical dosageregimen
❑Individualized dosage regimen
❑Dosage regimen on populationaverages
➢Fixed model
➢Adaptivemodel
Population
averages
➢Calculationsare
based on one
compartment
open model
➢Pharmacokinetic
parametersremain
constant during
the course of
therapy

8. Factors to beconsidered
 Pharmaceutical factors
o Type of dosageform
o Route of administration
 Patient related factors
o Individual patient’s tolerance of thedrug
o Geneticpredisposition
o Concurrent administration of otherdrugs
o Patient’s age, bodyweight,gender
o Length of illness
o General physical health
o Liver and kidney function in thepatient
DOSE SIZE
The magnitudeof both therapeuticand toxic responsesdepend upon
dose size. Dose size calculation requires the knowledge of amount of
drug absorbed afteradministrationof each dose

9.  Pharmacokineticfactors
Rate and extentof
▪ Absorption
▪ Distribution
▪ Metabolism and
▪ Excretion of drugs inpatients
DOSE FREQUENCY
Dose interval is
calculated on the
basis of the half lifeof
the drug. Increase or
decrease of the
dosing interval make
changes to the
average drug
concentration
attained in thebody

10. FACTORS AFFECTING DOSAGE INTERVAL
I. Half-life : dosage interval can generally beextended in relation to half-life
II. Therapeutic index : the highertheTI ,the longeran interval can be spaced with
higherdoses
III. Body clearance : to evaluateaccumulation
IV. Sideeffectswhich may require special administration times, e.g. bed time to
avoid sedation

11. STEP - A targetsteadystateconcentration is evaluated at first.
This is calculated from the maximum tolerabledoseand the minimum effective
concentration
Css,ave = Cupper -Clower / ln (Cupper/Clower )
It is slightlydifferent from thealgebraicaverageof maximumand minimum value
PHARMACOKINETIC BASED DESIGN OF DOSAGE
REGIMEN – IV BOLUS DOSING
Step 2 Estimation of the dosing rate (dose/τ) necessary to achieve Css ave
For this calculation, needs clearance(Cl) and extent of systemic availability(F) of
thedrug.
Dose / τ= Cl . Cssave/F
For iv dose F is 1 so theequation gets converted to productof clearanceand
average steady stateconcentration

12. STEP–3 Estimation of the maximum allowableτ(τmax)
The rate of decline in the plasma concentration from Cmax to Cmin is governed by
the drug elimination half life (t1/2) or elimination rate constant (K) Therefore, we
can estimate how long it would take for the plasma concentration to decline from a
maximum to a minimum
Css, min = Css, max *e-kτmax
The above equation can be rearranged to solve for τmax
τmax= ln (Css, max /Css, min ) / K
Dosing interval selected s always smaller then the τmax. τmax is the largest interval
selected for the patient. Practical decisions are taken regarding thedosing interval
STEP–4 Estimation of thedose
Knowing thedosing rate (dose/τ) and dosage interval (τ), wecan simplyestimate the
doseas
Dose = Dosing Rate x DosageInterval
If the dose is not practical or the available strengths would not allow the
administration of theexactdose, we may round it to the nearestpractical number

13. DRUG ACCUMULATION DURING MULTIPLE DOSING
During the multipledosing accumulation of thedrug takes place. This occurssincedrug
from the previousdose is notcompletely removed.
Accumulation is a functionof
➢ Dosing interval and
➢ Elimination half life
Accumulation index is givenas
Rac= 1/1-e-Kґ
Maintenance dose and loading dose is based on the accumulation index. Accumulation
index isalsoexpressed as the ratioof loading to the maintenancedose
Time to reacha steady
state depends
primarily on the half
life of the drug. When
Ka is greater than Ke
it the plateau is
reached
approximately 5 half
life

14. FLUCTUATION
Fluctuation is defined as the ratio of Cmax to Cmin. Greater the ratio greaterthe
fluctuation. It depends on dosing frequency and half life ofdrug
Controlled release of a drug is attained by decreasing the fluctuation.

15. LOADING AND MAINTANANCE DOSE
A drug does not show therapeutic
activity unless it reaches steady state. It
takes long time foradrug with long half
life to reachsteadystate. Forthis reason
loading doses followed by maintenance
dose are given to achieve steady state
rapidly.
Expression for loading dose isgiven as
XOL = Css, av*Vd
Expression for finding maintenance
dose
XO = Css, av* Cl*ґ
When bioavailability factor comesinto
vicinity as in case of extra vascular
administration both equations are
divided by F

16. PHARMACOKINETIC BASED DESIGN OF DOSAGE REGIMEN- iv infusion
This is thesimplestcase, as onedealswith the infusion rateconstant (R0) only (no need to estimate
τ)
Step-1 estimation of infusionrate
Thiscan bedone based on the required steadystateconcentration required
R0= Cl . Css
Step2 estimation of the loadingdose
Thiscan bedone multiplying with thevolumeof distribution. Usuallya loading dose isgiven and the
concentration is maintained bythe infusion rate
extravascular
➢The estimation of dose and dosing rate after extra vascular dosing (e.g., oral administration) is
more complicated than that after IV bolus doses because the rateand extent (F) of extravascular
availability would also be important factors in addition to other kineticparameters.
➢Because of the complexity of calculations involving absorption rate constant, in practice, the
absorption of most immediate release formulations is assumed to be instantaneous (ie F = 1). In
such casesdosecan becalculated bysameequationsas that of iv bolus

18. ➢ Step 1 calculation of average based on the therapeutic index
Css,ave = Cupper -Clower / ln (Cupper/Clower )
Thereforecssaverage isgiven as 14.43 mg/litre
➢ Step 2 calculation of dosingrate
Dosing rate = clearance *average steadystate
That is given as 14.43*2.6 which is 37.5mg
➢Step-3 Calculation of maximum timeinterval Maximum time interval is
givenby
τmax= ln (Css, max /Css, min ) /K
It was found to be8.059
➢ Step 4 calculation ofdose
Nowthedose isgiven as 8*37.5 which is 300mg Loading dose will be
14.43*30which is432.9
Taketheexampleof theophylline. Pharmacokineticdataobtained are
as follows
➢Therapeutic range is 10- 20 mg /litre
➢clearance=2.6litre/hour
➢Vol of distribution=30 l
➢Elimination rate constant=.086
➢T half= 8hours
PRACTICAL PROBLEM

19. DESIGN OF CONTROLLED RELEASE DRUG DELIVERY SYSTEM
 Basic rationale for controlled release drug delivery system is to optimize biopharmaceutical , pk and
pd propertiesof drug in suchawaythat its utility is maximized through reduction in side effects and
cure and control of disease condition in the shortest possibleway.
 Three main factors determiningare
➢ Biopharmaceticfactors
➢ Pkfactors
➢ Pdfactors
 Wewill focus on the pharmacokinetic factorson thedesignof the CRDDS
Biopharmaceutical
➢ Mol wt
➢ Aq solubility
➢ Partitioncoefficient
➢ Pka and ionizationat
physiological ph
➢ Drug permeability,stability
➢Mechanism and siteof
absorption
➢ Route of administration
Pharmacokinetic
➢Absorptionrate
➢Elimination half life
➢Rate of metabolism
➢Dosage form index
Pharmacodynamic
➢Drug dose
➢Therapeuticrange
➢Therapeuticindex
➢Pk-pd relation

20. KINETICS OF CONTROLLED RELEASE FORMULATION
 Controlled release forms are so designed that they release medicament over
prolonged period of time usually longer than the usual dosing interval for
conventional dosage form
 For controlled release fluctuation isreduced
 Rate controlling step is not absorption but the release from the formulation.
 One compartment models are usually used for the study of the
pharmacokinetics of controlled release formulations
 Reason for this is that the release of the drug from the formulation is slow. So
usually distribution is much faster compared to release. Thus one
compartment models can be usedsuccessfully
 Thus ADME follow a first order model. Rate of release from the dosage form is
zero order release or near zero order ie rate of input. This can be compared with
the iv infusion model

21. In order to maintain thedesired steadystateconcentration
the rate of input must be equal to the rate of elimination Ro
= R output
On assuming the zeroorderrate infusion model
Dm=Css*Cl*ґ/F
Thisequation can be used tocalculate the maintenance
dose of thedrug
Loading dose iscalculated as mentioned earlier by the
formula
Di= Css*Vd/F=R0/Ke
Total dose is given as the sum of the maintenancedoseand
the loading dose
KINETICS FOR THE CONTROLLED RELEASE
FORMULATION

22. DRUG RELEASE PATTERNS
 Drug disposition follow first orderkinetics
 Rate controlling step is drugrelease
 Released drug is rapidly and completely absorbed;
 Four models
➢ Slow zero orderrelease
➢ Slow first orderrelease
➢ Initial rapid releaseof loading dose followed byslow zeroorder
➢ Initial rapid followed by slow firstorder

23. SLOW ZERO ORDER+ RAPID
RELEASE COMPONENT
➢Immediate release in firstorder
followed by zero orderrelease
➢ Suitable for drugs with long halflife
➢Notgood forrepetitive dosing since it
shows peak trough pattern in between
which may result in the toxiceffects
➢Increasing the dosing interval
➢Decreasing the loading dose inthe
subsequentdoses
➢Administration of ir tablet atfirst
followed bysr
SLOW FIRST ORDER RELEASE +
RAPID RELEASE COMPONENT
➢Decreased absorption efficiency asthe
time passes.
➢Better sustained levels can be achieved
as theamount released decreases by time
and it is expected after the complete
release of immediate releasecomponents
a decreased maintenancedose