Pharmacokinetics - brief description

1. Prepared by: Christy P George

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. It also concerns the relationship
of these processes to the intensity and time course of pharmacologic
(therapeutic and toxicology) effects of drugs and chemicals.
 Pharmacokinetics is a quantitative study
The birth of pharmacokinetics really occurred in the 1920s and 1930s,
being marked by the classical papers of HAGGARD (1924) on the
disposition of 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 the drug
collection of
biological
samples and
obtaining the
data using
analytical
procedures
Analysis of data
Model approach Model independent approach
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 lesser side effects and
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
I. Design and dvpt of drugs with lesser side effects and
improved therapeutic effectiveness
II. Design and dvpt of optimum formulation for better use
of drug
III. Design and dvpt of targeted and controlled release
formulation
IV. Design of multiple dosage regimen
V. Selection of appropriate route of administration
VI. Select of right drug for particular illness
VII. Predict interactions
VIII.TDM
IX. Dosage adjustments at times of 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 therapeutic objectives.
 Duration of most illness is longer than a single dose. Therefore to prolong the
therapeutic effect multiple dosing dosage regimen is preferred.
An optimal dosage regimen is the one
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 dosage regimen
Individualized dosage regimen
Dosage regimen on population averages
Fixed model
Adaptive model
Population
averages

based on one
compartment
open model
Pharmacokinetic
parameters remain
constant during
the course of
therapy
Population
averages
Calculations are
based on one
compartment
open model
Pharmacokinetic
parameters remain
constant during
the course of
therapy

8. Factors to be considered
 Pharmaceutical factors
o Type of dosage form
o Route of administration
 Patient related factors
o Individual patient’s tolerance of the drug
o Genetic predisposition
o Concurrent administration of other drugs
o Patient’s age, bodyweight, gender
o Length of illness
o General physical health
o Liver and kidney function in the patient
DOSE SIZE
The magnitude of both therapeutic and toxic responses depend upon
dose size. Dose size calculation requires the knowledge of amount of
drug absorbed after administration of each dose

9.  Pharmacokinetic factors
Rate and extent of
 Absorption
 Distribution
 Metabolism and
 Excretion of drugs in patients
DOSE FREQUENCY
Dose interval is
calculated on the
basis of the half life of
the drug. Increase or
decrease of the
dosing interval make
changes to the
average drug
concentration
attained in the body

10. FACTORS AFFECTING DOSAGE INTERVAL
I. Half-life : dosage interval can generally be extended in relation to half-life
II. Therapeutic index : the higher the TI ,the longer an interval can be spaced with
higher doses
III. Body clearance : to evaluate accumulation
IV. Side effects which may require special administration times, e.g. bed time to
avoid sedation

11. STEP - A target steady state concentration is evaluated at first.
This is calculated from the maximum tolerable dose and the minimum effective
concentration
Css,ave = Cupper -Clower / ln (Cupper/Clower )
It is slightly different from the algebraic average of maximum and 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
the drug.
Dose / τ= Cl . Cssave /F
For iv dose F is 1 so the equation gets converted to product of clearance and
average steady state concentration

12. STEP–3 Estimation of the maximum allowable τ(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 τ max
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 the dosing interval
STEP–4 Estimation of the dose
Knowing the dosing rate (dose/τ) and dosage interval (τ), we can simply estimate the
dose as
Dose = Dosing Rate x Dosage Interval
If the dose is not practical or the available strengths would not allow the
administration of the exact dose, we may round it to the nearest practical number

13. DRUG ACCUMULATION DURING MULTIPLE DOSING
During the multiple dosing accumulation of the drug takes place. This
occurs since drug from the previous dose is not completely removed.
Accumulation is a function of
Dosing interval and
Elimination half life
Accumulation index is given as
Rac= 1/1-e-Kґ
Maintenance dose and loading dose is based on the accumulation
index. Accumulation index is also expressed as the ratio of loading to
the maintenance dose
Time to reach a 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 greater the
fluctuation. It depends on dosing frequency and half life of drug
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 for a drug with long half
life to reach steady state. For this reason
loading doses followed by maintenance
dose are given to achieve steady state
rapidly.
Expression for loading dose is given as
XOL = Css, av* Vd
Expression for finding maintenance
dose
XO = Css, av* Cl*ґ
When bioavailability factor comes into
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 the simplest case, as one deals with the infusion rate constant (R0) only (no
need to estimate τ)
Step-1 estimation of infusion rate
This can be done based on the required steady state concentration required
R0= Cl . Css
Step2 estimation of the loading dose
This can be done multiplying with the volume of distribution. Usually a loading dose
is given and the concentration is maintained by the infusion rate
extra vascular
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
rate and extent (F) of extra vascular availability would also be important factors in
addition to other kinetic parameters.
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 cases dose can be calculated by same equations as
that of iv bolus

18. Step 1 calculation of average based on the therapeutic index
Css,ave = Cupper -Clower / ln (Cupper/Clower )
Therefore css average is given as 14.43 mg/litre
Step 2 calculation of dosing rate
Dosing rate = clearance *average steady state
That is given as 14.43*2.6 which is 37.5mg
Step-3 Calculation of maximum time interval
Maximum time interval is given by
τmax= ln (Css, max /Css, min ) / K
It was found to be 8.059
Step 4 calculation of dose
Now the dose is given as 8*37.5 which is 300mg
Loading dose will be 14.43*30which is 432.9
Take the example of theophylline. Pharmacokinetic data obtained 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 properties of drug in such a way that its utility is
maximized through reduction in side effects and cure and control of disease
condition in the shortest possible way.
 Three main factors determining are
 Biopharmacetic factors
 Pk factors
 Pd factors
 We will focus on the pharmacokinetic factors on the design of the CRDDS
Biopharmaceutical
Mol wt
Aq solubility
Partition coefficient
Pka and ionization at
physiological ph
Drug permeability, stability
Mechanism and site of
absorption
Route of administration
Pharmacokinetic
Absorption rate
Elimination half life
Rate of metabolism
Dosage form index
Pharmacodynamic
Drug dose
Therapeutic range
Therapeutic index
Pk-pd relation

20. KINETICS OF CONTROLLED RELEASE FORMULATION
 Controlled release forms are so designed that they release medicament over




 Thus ADME follow a first order model. Rate of release from the dosage form is
rate of input. This can be compared with
 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 is reduced
 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 used successfully
 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 the desired steady state concentration
the rate of input must be equal to the rate of elimination
Ro = R output
On assuming the zero order rate infusion model
Dm=Css*Cl*ґ/F
This equation can be used to calculate the maintenance
dose of the drug
Loading dose is calculated as mentioned earlier by the
formula
Di= Css*Vd/F=R0/Ke
Total dose is given as the sum of the maintenance dose and
the loading dose
KINETICS FOR THE CONTROLLED RELEASE
FORMULATION

22. DRUG RELEASE PATTERNS
 Drug disposition follow first order kinetics



 Drug disposition follow first order kinetics
 Rate controlling step is drug release
 Released drug is rapidly and completely absorbed;
 Four models
 Slow zero order release
 Slow first order release
 Initial rapid release of loading dose followed by slow zero order
 Initial rapid followed by slow first order

23. Slow zero order release

absorption site

from all sites

rate of release from the CRDDS
Thus on overall as the release is zero
order absorption can also be marked
as zero order.
Similar to one compartment kinetics
following constant rate iv infusion


Slow zero order release
Drug released is stable in fluids at
absorption site
Absorbed completely and rapidly
from all sites
Rate of appearance is governed by
rate of release from the CRDDS
Thus on overall as the release is zero
order absorption can also be marked
as zero order.
Similar to one compartment kinetics
following constant rate iv infusion
It takes time to reach steady state
Ideal dosage form
Slow first order release
As the drug advances along the git the
absorption and release decreases
Inferior to zero order release. Higher
Cmin and lower Cmax is observed
Flip flop phenomena is observed
Slow first order release
As the drug advances along the git the
absorption and release decreases
Inferior to zero order release. Higher
Cmin and lower Cmax is observed
Flip flop phenomena is observed

24. SLOW ZERO ORDER+ RAPID
RELEASE COMPONENT
Immediate release in first order
followed by zero order release
Suitable for drugs with long half life
Not good for repetitive dosing since it
shows peak trough pattern in between
which may result in the toxic effects
Increasing the dosing interval
Decreasing the loading dose in the
subsequent doses
Administration of ir tablet at first
followed by sr
SLOW FIRST ORDER RELEASE +
RAPID RELEASE COMPONENT
Decreased absorption efficiency as the
time passes.
Better sustained levels can be achieved
as the amount released decreases by time
and it is expected after the complete
release of immediate release components
a decreased maintenance dose

25. reference
 Brahmankar and jaiswal; biopharmaceutics and
pharmacokinetics a treatise