For Class- B.

Pharmacy 6th Semester

Subject- BIOPHARMACEUTICS AND PHARMACOKINETICS (BP604T)

RAMAKANT JOSHI
School of Studies in Pharmaceutical Sciences,
Jiwaji University, Gwalior
 Pharmacokinetic modeling is a
mathematical modeling technique for
predicting the absorption, distribution,
metabolism and excretion (ADME) of
synthetic or natural chemical substances in
humans and other animal species.
• Drug movement within the body is the
complex process to describe and for analysis.

• So two major approaches in the quantitative

study of various kinetic processes of drug
disposition in the body are:

1. Model approach, and

2. Model-independent approach (non-

compartmental analysis)
 Methods for analysis
of pharmacokinetic
data

Model
Model approach independent
approach

Compartment Physiological Non-

Distributed compartm
model model parameter ent
1. Mammillary 1.perfusion- model analysis
model limited model
2. Catenary 2.diffusion-
model limited model
 In this approach, models are used to describe
changes in drug concentration in the body with
time.
PHARMACOKINETIC MODEL:
Pharmacokinetic model provides mathematical
expression for the time course of drugs
throughout the body and compute meaningful
pharmacokinetic parameters.
* Compartm Physiological Distributed
ent models models parameter
• Empirical • Realistic models models
models • Realistic models
 Compartment analysis is the traditional and
most commonly used approach to
pharmacokinetic characterization of a drugs.
 These models simply interpolate the
experimental data and allow an empirical
formula to estimate the drugs concentration
with time
 Since compartments are hypothetical in
nature ,compartments models are based n
certain assumptions.
1. The body is represented as a series of
compartments arranged either in series or
parallel to each other,which communicate
reversibly with each other.
2. Each compartment is not a real physiological or
anatomical region but fictitious or virtual one
and considered as a tissue or group of tissue
that have similar drug distribution
characteristics
3. Within each compartments the drugs is
considered to be rapidly and uniformly
distributed
4. The rate of drug movement between
compartments described by first order kinetics
 Depending upon whether the compartment
are arranged parallel or in series
,compartments models are divided into two
categories –
 Mammillary model
 Catenary model
 Itconsists of one or more peripheral
compartments connected to the central
compartment in a manner similar to
connection of satellites to a planet
 They are joined parallel to the central
compartment
 The central compartment comprises of
plasma and highly perfused tissues such as
lungs, liver, kidney etc. which rapidly
equilibrate with drugs.
Central
compartment
 The compartments are joined to one another
in a series like compartments of a train.

 Itis rarely used because it is not observed

that anatomically or physiologically various
organs are directly linked to the blood
compartment.
 They are drawn on the basis of known
anatomical and physiological data
 So it present more realistic picture of
drug disposition in various organs and
tissues.
 Tissues with similar perfusion properties
are grouped into a single compartment
 e.g. lungs, liver, brain and kidney are
grouped as rapidly equilibrating tissues
 While muscles and adipose as slowly
equilibrating tissues.
 It is analogous to physiological model but
has been designed to take into account
 Variations in blood flow to an organ
 Variations in drug diffusion in an organ
 The distributed parameter model differ from
physiological model in that the mathematical
equation are more complex and collection of
drug concentration data is more difficult.
 k/as model independent methods

 Because it does not require the assumption

of specific compartment model.

 Thismethod is based on the assumption that

the drugs or metabolites follow linear
kinetics,

 Sothis technique can be applied to any

compartment model.
 Based on statistical moments theory

 It involves collection of experimental data

following a single dose of drug

 If one consider the time course of drug

concentration in plasma as a statistical
distribution curve, then

MRT= AUMC/AUC
 Where
MRT= mean residence time
AUMC= area under the first moment
curve
AUC= Area under the zero moment curve

MRT= is defined as the average amount of time

spent by the drug in the body before being
eliminated.

AUMC and AUC can be calculated from the use

of trapezoidal rule.
 Characterizing the behavior of drugs in
patients.
 Correlating plasma drug concentration with
pharmacological response.
 Evaluating the bioequivalence\
bioinequivalence between different
formulations of the same drugs.
 Determining the influence of altered
physiology\disease state on drugs ADME
 Explaining drugs interaction.
ONE-COMPARTMENT OPEN MODEL
(INSTANTANEOUS DISTRIBUTION MODEL)
The one-compartment open model is the simplest model.
1. Elimination is a first-order (monoexponential) process with first-order rate constant.
2. Rate of input (absorption) > rate of output (elimination).
3.The anatomical reference compartment is plasma and concentration of drug in
plasma is representative of drug concentration in all body tissues i.e. any change in
plasma drug concentration reflects a proportional change in drug concentration
throughout the body.
However, the model does not assume that the drug concentration in plasma is
equal to that in other body tissues.
 The general expression for rate of drug presentation to the body is:

dX
= Rate in (availability) - Rate out (elimination)
dt

dX
= − K Ε X
dt
Elimination phase can be characterized by 3 parameters—
1. Elimination rate constant
2. Elimination half-life
3. Clearance.

Elimination Rate Constant:

ln X = ln Xo – KE t

The above equation shows that disposition of a drug that follows one-compartment
kinetics is monoexponential.
X = Xo e–KEt

X = Vd C
KE t
log C = log C 0 -
2.303
 KE = Ke + Km + Kb + Kl + ......

if a drug is eliminated by urinary excretion and metabolism only, then, the fraction of
drug
excreted unchanged in urine Fe and fraction of drug metabolized Fm can be given as:

Ke Km
Fe = Fm =
KE KE
Elimination Half-Life: 0.693
t1/2 =
KE

0.693 Vd
t1/2 =
Cl T

• Apparent volume of distribution, and

• Clearance.
Since these parameters are closely related with the physiologic mechanisms in the bo
they are called as primary parameters.
Amount of drug in the body X
Vd = =
Plasma drug concentration C

X0 i.v.bolus dose
Vd = =
C0 C0
Clearance is defined as the theoretical volume of body fluid containing drug (i.e. that
fraction of apparent volume of distribution) from which the drug is completely removed
in a given period of time. It is expressed in ml/min or liters/hour.

Rate of elimination by kidney

ClR =
C

Rate of elimination by liver

ClH =
C

Rate of elimination by other organs

Cl Others =
C
 Cl *
0 . 6 9 3 Vd
T
t 1/2

For drugs given as i.v. bolus

X0
Cl T =
AUC

For drugs given e.v.

FX 0
C lT =
AUC
 dX
= R 0 − K EX
dt

R
X = 0 (1 − e - K E t )
K E

R0 R
C= (1 − e-KEt ) = 0 (1 − e-KEt )
KE Vd ClT

R0 R Infusion rate
Css = = 0 i.e.
K E Vd ClT Clearance
One-Compartment Open Model: Extravascular Administration

dX/dt = Rate of absorption – Rate of elimination

dX dXev dX E
= −
dt dt dt

K FX
[
X = a 0 e-KEt - e-Kat
(Ka - KE )
] C=
K a F X0
Vd (Ka - KE )
[
e-KEt - e-Ka t ]
At peak plasma concentration, the rate of absorption equals rate of
elimination i.e. KaXa = KEX
dC = Ka FX0
dt Vd (Ka - KE )
[
- K E e-K E t + K a e-Kat ] = Zero

K E e -K E t = K e -K a t
a

KE t K t
log K E - = log K a - a
2.303 2.303

2.303 log (K a /K E )
t max =
Ka - K E

F X 0 -K E t m ax
C m ax = e
Vd
Absorption Rate Constant: It can be calculated by the method of residuals. The technique
is also known as feathering, peeling and stripping. It is commonly used in
pharmacokinetics to resolve a multiexponential curve into its individual components. For a
drug that follows one-compartment kinetics and administered e.v., the concentration of
drug in plasma is expressed by a biexponential equation.

C=
Ka F X0
Vd ( K a - K E )
[
e -K E t - e -K a t ]

C = A e -K E t
 KE t
log C = l o g A -
2.3 0 3

( C - C) = Cτ = A e -K a t

Ka t
log C τ = l o g A -
2.303
 The method involves determination of Ka from percent unabsorbed-time plots and does
not require the assumption of zero- or first-order absorption.
X A = X + X E

X =K V [AUC] t
E E d 0

X = V C + K V [AUC]t
A d E d 0

X ∞ = V C ∞ + K V [AUC] ∞
A d E d 0

X∞ =K V [AUC]∞
A E d 0

XA V d C + K E V d [ AUC] t0 C + K E [A U C ] t0
= =
X ∞A K E V d [ A U C ] ∞0 K E [A U C ] ∞0

 XA   C + K E [AUC] t0 
%ARA = 1 - ∞  100 = 1 −  100
 X A   K E [AUC] ∞
0 
 INFLUENCE OF KA AND KE ON CMAX, TMAX AND
AUC
Parameters Influence when KE is Influence when Ka is
affected constant constant

Smaller Ka Larger Ka Smaller KE Larger KE

Cmax ↓ ↑ ↑ ↓

tmax Long Short Long Short

AUC No Change No Change ↑ ↓

Criteria for Obtaining Valid Urinary Excretion Data
A significant amount of drug must be excreted unchanged in the urine (at least 10%).
1. The analytical method must be specific for the unchanged drug; metabolites should not interfere.
2.Water-loading should be done by taking 400 ml of water after fasting overnight, to promote diuresis and
enable collection of sufficient urine samples.
3. Before administration of drug, the bladder must be emptied completely after 1 hour from water-
loading and the urine sample taken as blank. The drug should then be administered with 200 ml of water
and should be followed by 200 ml given at hourly intervals for the next 4 hours.

4. Volunteers must be instructed to completely empty their bladder while collecting urine samples.
5. Frequent sampling should be done in order to obtain a good curve.
6. During sampling, the exact time and volume of urine excreted should be noted.
7.An individual collection period should not exceed one biological half-life of the drug and ideally should
be considerably less.
8.Urine samples must be collected for at least 7 biological half-lives in order to ensure collection of more
than 99% of excreted drug.

9. Changes in urine pH and urine volume may alter the urinary excretion rate.
 *
1. Rate of excretion method, and
2. Sigma-minus method.
Rate of Excretion Method: The rate of urinary drug excretion dXu/dt is proportional
to
the amount of drug in the body X and written as:
dX u
= K eX
dt
According to first-order disposition kinetics, X = Xo e–KEt

dX u
= Ke X 0 e -K E t
dt

dXu KEt
log =log K X -
e 0
dt 2.303
Sigma-Minus Method: A disadvantage of rate of excretion method in estimating KE is that
fluctuations in the rate of drug elimination are observed to a high degree and in most
instances, the data are so scattered that an estimate of half-life is difficult. These problems
can be minimized by using the alternative approach called as sigma-minus
method. dX u
= K e X 0 e -K E t
dt
K X
X u = E 0 (1 - e -K E t )
KE

Xu = cumulative amount of drug excreted unchanged in urine at any time t. As time approaches
infinity i.e. after 6 to 7 half-lives, the value e–KE∞ becomes zero and therefore the cumulative amount
excreted at infinite time Xu ∞ can be given by equation

K eX
X ∞
u = 0
KE
X ∞
u - X u = X ∞
u e -K Et
KEt
log (X ∞u - X u ) = log X ∞u -
2.303
(Xu∞ – Xu) = amount remaining to be excreted
i.e. ARE at any given time.

A semilog plot of ARE versus t yields a straight line with slope -KE/2.303.

The method is, therefore, also called as ARE plot method.

A disadvantage of this method is that total urine collection has to be carried

out until no unchanged drug can be detected in the urine i.e. upto 7 half-lives,
which may be tedious for drugs having long t½.