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PRESENTATION ON

PHARMACOKINETIC PARAMETERS

PRESENTED TO:

Dr. Yasmeen Sultan
Department of pharmaceutics PRESENTED BY:
Jamia Hamdard

Dipak Kumar Gupta
M.pharm – Ist semester
SPER, Jamia Hamdard

 

INTRODUCTION
• The predictive capability of a pharmacokinetic model lies in the proper selection and

development of mathematical functions called parameters that govern a pharmacokinetic
process.

• In practice, pharmacokinetic parameters are determined experimentally from a set of drug
concentrations collected over various times known as data. Parameters are also known as
“variables”.

Variables are of two types:-

1.Independent variables

2.Dependent variables

 

TYPES OF PARAMETERS

1.INDEPENDENT VARIABLES:-Variables
which are not affected by any other

parameter.

FOR EXAMPLE:- Time

2.DEPENDENT VARIABLES:-Variables
which change as the independent variables

change.

FOR EXAMPLE:-Plasma
drug concentration

 

APPLICATION OF PARAMETERS IN
PHARMACOKINETIC STUDIES

The number of parameters More the number For the
needed to describe the of parameters pharmacokinetic
pharmacokinetic model more are the parameters to be valid,

depends upon the the number of data
complexity of the difficulties in points should always

pharmacokinetic process & accurate estimation exceed the number of
on the route of drug of these parameters of the

administration parameters pharmacokinetic model

 

PHARMACOKINETIC PARAMETERS GENERATED
AFTER ADMINISTRATION OF DRUG

1.AREA UNDER CURVE(AUC):-It is a measure of the extent of drug absorption from the
administered drug dose into the systematic circulation

2.BIOLOGICAL HALF LIFE(t1/2):-It is an indicator of time needed for the plasma drug
concentration to decline by 50%.

3.CLEARANCE:-It is a theoretical concept . This concept is used for describing elimination
of the drug from the body without identifying specific mechanism of the process of drug
elimination.

4.FRACTION OF ADMINISTERED DOSE ABSORBED(F):-It is a measure of the extent dose
administered dose that actually reaches systemic circulation .Sometimes fraction of dose
absorbed is also referred to as relative bioavailability or simply bioavailability

5.MAXIMUM CONCENTRATION OF DRUG IN PLASMA(Cmax):-It is the peak
concentration of drug plasma concentration attained after the administration of a given
dose.

 

6. MEAN ABSORPTION TIME(MAT):- It describes the average time for all the drug molecules to be
absorbed from the site of administration . It applies only to the extravascularly administered drugs.

7. MEAN RESIDENCE TIME(MRT):-It describes the average time for all the drug molecules of a given dose
to reside in the body.

8. RATE CONSTANT OF ABSORPTION OF DRUG(Ka):- It is the measure of the rate at which the drug is
absorbed after it has become available for absorption.

9. RATE CONSTANT OF METABOLISM OF DRUG(Km):-It is the rate at which drug is metabolized or
biotransformed in the body.

10. RATE CONSTANT OF ELIMINATION OF DRUG(Ke):-It is there at which the drug is removed from
the body by an excretory process.

11. RATE CONSTANTS OF TRANSFER OF DRUG BETWEEN PLASMA AND TISSUES (K12,K21,etc):- It
indicate rates at which drug moves between plasma and body fluids or tissues.

 

12. STEADY STATE CONCENTRATION OF THE DRUG( Css ):- It indicates that on
chronic administration of the drug dose , the concentration of drug in plasma attains a
plateau level.

13. APPARENT VOLUME OF DISTRIBUTION (Vd ):- It represents a hypothetical volume
of body fluid in which the drug appears to be dissolved.

 

AREA UNDER CURVE(AUC)
 The AUC (from zero to infinity) represents the total drug exposure over time. Assuming

linear pharmacodynamics with elimination rate constant K, one can show that AUC is
proportional to the total amount of drug absorbed by the body. The proportionality
constant is 1/K.

 This is useful when trying to determine whether two formulations of the same dose
(for example a capsule and a tablet) release the same dose of drug to the body.
Another use is in the therapeutic drug monitoring of drugs with a narrow therapeutic
index.

 AUC becomes useful for knowing the average concentration over a time interval,
AUC/t. Also, AUC is referenced when talking about elimination. The amount
eliminated by the body (mass) = clearance (volume/time) * AUC (mass*time/volume).

 

AUC & BIOAVAILABILITY
 In pharmacokinetics, bioavailability generally refers to the fraction of drug

absorbed systemically, and is thus available to produce a biological effect. This
is often measured by quantifying the “AUC”. In order to determine the
respective AUCs, the serum concentration vs. time plots are typically gathered
using C-14 labeled drugs and AMS (accelerated mass spectroscopy).

 Bioavailability can be measured in terms of “absolute bioavailablity” or “relative
bioavailablity “.

ABSOLUTE BIOAVAILABILITY

Absolute bioavailablity refers to the bioavailability of drug when administered via a
non-intravenous (non-IV) dosage form (i.e. oral tablet, suppository, subcutaneous,
etc.) compared with the bioavailability of the same drug administered
intravenously (IV). This is done by comparing the AUC of the non-intravenous
dosage form with the AUC for the drug administered intravenously. This fraction
is normalized by multiplying by each dosage form’s respective dose

Fabs=(AUCnon-iv/AUCiv)x(DOSEiv/DOSEnon-iv)

 

 RELATIVE BIOAVAILABILITY

Relative bioavailability compares the bioavailability between two different dosage
forms. Again, the relative AUCs are used to make this comparison and relative
doses are used to normalize the calculation.

Frel=(AUCdosage A/AUCdosageB)X(DOSEb/DOSEa)

 

METHODS FOR DETERMINATION
OF AUC

1.PHYSICAL METHODS

a)CUT AND WEIGHT METHOD

b)PLANIMETER

2.TRAPEZOIDAL METHOD

3.INTEGRATION METHOD

 

1.PHYSICAL METHODS

1.CUT AND WEIGH
METHOD

In this method the curve was plotted, it was cut out
and weight at the electronic meter and weight is

considered to be AUC.

2.PLANIMETER

It is the instrument by which the graph
is measured AUC was determined

 

TRAPEZOIDAL METHOD

 Trapezoidal method:- In this the plasma drug concentration versus time is
plotted on an ordinary cartensian graph paper , it is divided into several
trapezoids at the time of sampling points .

 The area of individual trapezoid is calculated and summed to get the Area Under
Curve

Area =1/2(Cn-1 + Cn ) ( tn – tn-1)

 If the sampling is done at equal interval of time then formula applied is: Area =
∆t/2 (C1+ 2C2………….2Cn-1+Cn)

 A general formula is Area =∑ Cn-1 + Cn /2( tn – tn-1)

 

INTEGRATION TIME

 Integration method:- In order to calculate AUC from time t to ∞
an integration of equation-

 C = Co.e -kt with respect to time is carried

 AUC=Co/k

 

BIOLOGICAL HALF LIFE(t1/2)
 The biological half-life or terminal half-life of a substance is the time it

takes for a substance (for example a metabolite, drug, signalling molecule,
radioactive nuclide, or other substance) to lose half of its pharmacologic,
physiologic, or radiologic activity. Typically, this refers to the body’s cleansing
through the function of kidneys and liver in addition to excretion functions
to eliminate a substance from the body.

 In a medical context, half-life may also describe the time it takes for the
blood plasma concentration of a substance to halve (plasma half-life) its
steady-state. The relationship between the biological and plasma half-life of a
substance can be complex depending on the substance in question, due to
factors including accumulation in tissues (protein binding), active metabolites,
and receptor interactions.

 

RATE EQUATIONS

1.FIRST ORDER REACTION

There are circumstances where the half-life varies with the concentration of
the drug. Thus the half-life, under these circumstances, is proportional to the
initial concentration of the drug A0 and inversely proportional to the zero-
order rate constant k0 where:

t1/2=0.5A0/k0

The fall in plasma concentration after the administration of a single dose is
described by the following equation:

Ct=C0e
-kt

Where

Ct=conc. after time t

C0=Initial concentration

k=elimination rate constant

 

 Half-life is determined by clearance (CL) and volume of distribution
(VD) and the relationship is described by the following equation:-

 t1/2=ln2.VD/CL

2. BIPHASIC HALF LIFE

Many drugs follow a biphasic elimination curve — first a steep slope
then a shallow slope

STEEP(initial part of curve)=initial distribution of drug in the body

SHALLOW=ultimate excretion of drug which is dependent on the
release of from tissue compartments into the blood

 

CLEARANCE
 The clearance is a pharmacokinetic measurement of the volume of plasma

from which a substance is completely removed per unit time; the usual units are
mL/min. The quantity reflects the rate of drug elimination divided by plasma
concentration

 Clearance is variable in zero-order kinetics because a constant amount of the
drug is eliminated per unit time, but it is constant in first-order kinetics, because
the amount of drug eliminated per unit time changes with the concentration of
drug in the blood

 Relation between clearance , intravenous dose & AUC

CL=Div/AUC

 

Mean residence time(MRT)

 It can be used to estimate the average time a drug molecule spends in
the body. It can also be used to help interpret the duration of effect of
direct acting molecule.

 It should be noted that MRT is highly influenced by the measurements in
the terminal phase

 If there will be inadequate samples to accurately estimate the terminal
elimination rate constant, MRT estimates will be unreliable

 MRT=AUMC/AUC

 Relation to half life after intravascular bolus

 t1/2=0.693.MRTiv

 

Mean absorption time
 MAT Stands for mean absorption time.

 MAT=MRTniv-MRTiv

 Difference between mean residence times after non-intravenous and
intravenous administration of drug solution

 Mean dissolution time MDT

 MDT=MATtabl-MATsol

 Difference between the mean absorption times after the oral administration
of a drug in a tablet & in a solution.

 

VOLUME OF DISTRIBUTION

 The volume of distribution is the amount of drug in the
body divided by plasma concentration

 Vd=X/C

 It is the apparent volume of a solution required to obtain
the observed plasma concentration.