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.