Pharmacokinetics Calculation

Pharmacokinetics Calculations
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Department of Pharmaceutics
KLE Universitys College of Pharmacy
BELGAUM- 590010, Karnataka, India
Cell No: 0091 974243100
E-mail: bknanjwade@yahoo.co.in
26-11-2010 KLECOP, Nipani 1

Introduction :
Pharmacokinetic Parameters:
Elimination rate constant

Biological Half life
Rate constant of absorption
Apparent volume of distributions
Area under the curve

Example : 1
Time (hrs) Conc (mcg/ml)
The plasma
concentration after the 1.0 8.0
250 mg intravenous 2.0 6.3
bolus dose of an 3.0 4.9
antibiotic is given below. 4.0 4.0
Plot the data and 5.0- 3.2
describe the
6.0 2.5
pharmacokinetic model.
7.0 1.9

Solution :
Graph

Elimination rate constant :
Suppose we choose the following two points to determine
the slope of the straight line :
x1= 0 hr, y1 = 10.0 mcg/ml, and x2 = 7.0hr, y2 = 2.0
mcg/ml. then
ln y2 ln y1 ln2.0 ln 10.0 0.6931 2.3026

Slope = = =
x2 x1 7.0 hr 0 hr 7.0 hr
- 1.6095
= = - 0.2299/ hr
7.0 hr
Therefore Ke = - slope = - (-0.2299/hr) = 0.2299/hr

Biological half-life :
Ke = 0.693
t1/2 , therefore
0.693
t =
Ke
0.693
= = 3.01 hr
0.2299/hr

Area under curve :
Area from 0 to 7.0 hours
AUC0-7.0 by trapezoidal rule = 34.85 mcg.hr/ml
AUC0-7.0 by counting squares = 34.85 mcg.hr/ml
AUC0-7.0 by Cutting and Weighing = 34.85 mcg.hr/ml

Total area under curve :
This is a two step method, first determine AUC0-7.0 ,
then determine AUC7.0-
Ct 2.0mcg/ml
AUC 7.0- = = = 8.7 mcg. hr/ml
Ke 0.2299/hr
Adding this value to AUC 0-7.0, we have
AUC0-infi = AUC0-7.0 + AUC7.0-

= 34.85mcg.hr/ml + 8.7mcg.hr/ml
= 43.50mcg.hr/ml
C0 10mcg / ml
AUC0- = = = 43.55 mcg.hr /ml
Ke 0.2299/ hr
Volume of distribution :
Dose
Vd =
Co
250 mg
=
10 mcg / ml
250 mg
=
10 mg/L
= 25 L

Description of model :
It shoes that a 250mg dose is administered

intravenously. The apparent volume of
distribution is 25 L and the rate constant of
elimination (Ke) is 0.2299 / hr. since biological
half-life is 3.01 hr.
intravenous
250 mg 25 LITRES
injection
0.2299 / hr
Example 2
The plasma concentration versus time data
following the administration of a single 250 mg
rapid intravenous bolus dose of a drug is
represented by the biexponential equation;
C = 1.5e-0.13t + 12.5 e1.3t.
Draw a schematic of the pharmacokinetic model,

assuming concentration is in mcg / ml and time
is in hours.
Solution
From the biexponential equation, the following parameters
of the two compartment pharmacokinetic model are
deduced : b= 0.13/hr (because the smallest hybrid rate
constant always b), and B = 1.5 mcg/ml (because B is y-
intercept corresponding to b). therefore a must be equal to
1.3/hr, and A = 12.5mcg/ml.
In order to draw a schematic of the pharmacokinetic

model, the following parameters need to be calculated:
rate constants K10, K12, K21,, and apparent volumes of
distribution Vc, and Vt.

Rate constants
Ab + Ba 1.625 + 1.95 3.575
K 21 = = = = 0.2554/hr
B+A 1.5 + 12.5 14.0
ab (1.3/hr) ( o.13/hr) 0.169/hr

K10 = = = =0.6617/hr
K21 0.2554/hr 0.2554/hr
K12 = a + b K21 K10
K12 = 1.3 /hr + 0.13 /hr 0.2554 / hr 0.6617 / hr
K12 = 0.5433 / hr

Apprent volume of distribution
D 250 mg
Vc = = = 17.857 L
B+A 14 mcg ml
Vc (K12 + K21)
Vd =
K21
(17.857 L) (0.5433 / hr+ 0.2554 / hr) 14.2624 L = 55.843 L

Vd = =
0.2554 / hr 0.2554
Vt = Vd Vc = 55.843 L 17.857 L = 37.986 L
(Vc) (K12) (17.857 L) (0.5433 / hr)

Vt = = = 37. 986 L
K21 0.2554 /hr
Schematic representation :
This schematic shows that the 250 mg dose can was
given intravenously. The apparent volume of the central
and tissue compartment are 17.857 L and 37.986 L,
respectively.
The first-order rate constant of transfer of the from the

central compartment into the tissue compartment is
0.5433 /hr and the first-order rate constant of transfer of
drug from the tissue compartment in to the central
compartment is 0.2554 / hr. the first-order rate constant
of elimination of drug from the central compartment is
0.6617 / hr.

Schematic of the two compartment model
0.5433/hr
intravenous 17.857 L
250 mg 37.986 L
injection 0.2554/hr
0.6617
/hr

Example -3
The following data TIME (Hr) Concentration (mcg/ml)
were obtained when a 1 26.501

500 mg dose of an 2 36.091
antibiotic was given 3 37.512
orally. Calculate the 4 36.055
pharmacokinetic 5 32.924
parameters, 6 29.413
assuming 100% of 8 22.784
the administered dose 16 7.571
was absorbed. 18 5.734
20 4.343
Graph

Solution:
Elimination rate constant:
The rate constant of elimination is calculated
from the terminal linear portion of plasma
profile.
To determine it, we need to calculate slope of
the straight line having y-intercept = B. if
natural log are used the rate constant of
elimination (b) = negative slope of this straight
line.
Therefore
ln 5.734 - ln 4.343 0.2778 = 0.139/ hr
b = - slope = - = -
(18 - 20) hr 2 hr
Biological half life:
The biological half life (t1/2) is determined using the

equation
t1/2 = 0.693/b
=
0.693
0.139/hr
= 4.98 hr
The Y-intercept, B
The Y-intercept of this straight line is B and is
determined using the first order equation
ln Ct = ln B bt
Which upon rearrangement gives

ln B = ln Ct + bt
= ln 4.343 + (0.139/hr)(20hr)
=1.4686 + 2.78
= 4.2486
B = Inverse ln 4.2486
= 70.0 mcg/ml
Feathering the curve :
To obtain the straight line which represents absorption
phase, the technique of feathering or the method of
residuals is used. for example, to feather the first plasma
conc. point at 1 hr, the plasma conc. at 1 hr on the
straight line having the y intercept = B is subtracted from
the plasma conc. data provided in the data.
ln Ct = ln B - bt
ln Ct = ln 70 (0.139) (1)
= 4.2485 0.139
= 4.1095
Ct = inverse ln 4.109 = 60.916 mcg/ml
Graph

The residual conc. at 1 hr is obtained by subtracting from
this concentration at 1 hr provided in the data.
therefore the residual concentration at 1hr is,
1 hr = 60.916 26.501
= 34.415mcg/ml

The rate constant of absorption is obtained from the

slope of the straight line which represent absorption as
follows;
ln 70 ln 0.1
Ka = a = - slope =-
0 hr 9.22 hr
=- 6.5511
- 9.22 hr
= - 0.71/ hr

Apparent volume of distribution
Since 100% of the administstered dose was absorbed,

F = 1. substittuting the values of B= 70mcg/ml, D= 50mg,
a = Ka = 0.71/hr, b Ke = 0.139/hr,
(F)(D)(a)
B=
(Vd)(a-b)
(1)(500mg)(0.71/hr)
70 mcg/ml=
(Vd)(0.71/hr 0.139 /hr)
621.72 mg
(Vd) =
70mcg / ml = 8.88 L

Area under the curve
B - A 70 mcg/ml - 70 mcg/ml
AUC = =
b a 0.139/hr 0.71/hr
AUC = 503.597 mcg hr/ml 98.592 mcg hr /ml
= 405.005 mcg hr/ml

Description of the model
Schematic shows that a 500 mg of the dose of the drug
was administered by an extravascular route. The first-
order rate constant of absorption is 0.71/hr and the first
order rate constant elimination is 0.139/hr. the apparent
volume of the central compartment is 8.88 L.
0.71 /hr
500 mg 8.88 LITRS
0.139 / hr
Example -3.1
From the data given TIME (Hr) Concentration (mcg/ml)
Calculate the time 1 26.501

when administered 2 36.091
drug dose reaches its 3 37.512
maximum 4 36.055
concentration in the 5 32.924
plasma. 6 29.413
8 22.784
16 7.571
18 5.734
20 4.343

From the pharmacokinetic parameters found, the first-
order rate constant of absorption, Ka = 0.71/hr and the
first order rate constant elimination, Ke = 0.139/hr.
ln Ka ln Ke
t max = Ka Ke
ln 0.71 /hr ln 0.139 /hr

t max =
0.71 /hr 0.139 /hr
0.3425 (- 1.9733) 1.6308

t max = = = 2.856 hr
0.571 /hr 0..571 /hr

Example -3.2
From the data given TIME (Hr) Concentration (mcg/ml)
Calculate the 1 26.501

maximum 2 36.091
concentration of the 3 37.512
drug in plasma 4 36.055
attained after the 5 32.924
administration of the 6 29.413
dose. 8 22.784
16 7.571
18 5.734
20 4.343

B = 70 mcg /ml, Ka = 0.71 /hr, Ke = 0.139 /hr,
and tmax = t = 2.856 hr
C max = B (e-bt e-at)
C max = (70 mcg/ml) (e-(0.139/hr))(2.856 hr) e-(0.71/hr)(2.856hr))
C max = (70 mcg/ml) (0.623 0.1316)
C max = (70 mcg/ml) (0.5407)
= 37.85 mcg ml

Example -4
The following data TIME (Hr) Concentration (mcg/ml)
were obtained when a 2 3.915

500 mg dose of an 4 8.005
antibiotic was given 6 7.321
orally calculate the 8 5.803
pharmacokinetic 10 4.403
parameters, 16 1.814
assuming 100% of 18 1.344
the administered dose 20 0.996
was absorbed. 24 0.546
28 0.300

graph

Elimination rate constant:
The rate constant of elimination (b) is
calculated using the terminal two points of the
plasma profile as follows;
Therefore
ln 0.546 mcg/ml - ln 0.300 mcg/ml

b = - slope =-
(24 - 28) hr
0.5988 = 0.15/ hr
=-
4 hr
The y-intercept, b, of this straight line is determined
using the first-order rate equation :
B = Ct e bt = (0.3 mcg/ml) e(0.15/hr)(28hr)
B = (0.3 mcg/ml) (66.6863)
B = 20 mcg/ml

To obtained the straight line which represents absorption
phase, the technique of feathering is used. The plasma
profile is feathered with respect to the straight line having
y-intercept = B. To feather the first concentration point,
the concentration at 2 hr on the straight line having y-
intercept = B is subtracted from the data concentration at
2 hr.
C = Be-bt = (20 mcg/ml)e-(1.5/hr)(2hr)
C = (20 mcg/ml) (0.7408) = 14.816 mcg/ml
Therefore, residual concentration at 2 hr is :
14.816 mcg/ml 3.915 mcg/ml = 10.901 mcg/ml

Biological half life:
The biological half life (t1/2) is determined using the

equation
t1/2 = 0.693/b
=
0.693
0.15/hr
= 4.62hr
The rate constant of absorption is obtained from the
slope of the straight line having the y-intercept = A. It is
calculated as follows;
ln 40 mcg/ml ln 0.221 mcg/ml

Ka = a = - slope =-
0 hr 8 hr
= 5.198
8hr
= 0.65/ hr

Lag-Time
Since the value of the y-intercept A is not equal to the

value of the y-intercept B, the dosage from exhibits lag-
time. The lag-time (L) is determined using equation
ln A ln B
L =
ab
ln 40 mcg/ml ln 0.20 mcg/ml

=
0.65 0.15
0.693
=
0.5 / hr
= 1.386 hr
The equation for calculating the time of maximum
concntration of drug in plasma in presence of lag-time,
tmax (L), is
ln A ln B + ln a ln b
t max =
a-b
ln 40 ln 20 + ln 0.65 ln 0.15
t max =
0.65 /hr 0.15 /hr
1.4663
t max = = 4.319 hr
0.5 /hr

C max (L) = Be-bt Ae-at)
C max (L) = (20 mcg/ml) (e-(0.15/hr))(4.319 hr) e-(0.65 /hr)(4.319 hr))
C max (L) = (20 mcg/ml) (0.5253) (40 mcg /ml) (0.0604)
C max (L) = 10.463 mcg/ml 2.415 mcg /ml
C max (L) = 8.048 mcg /ml

Pharmacokinetics
and
Pharmacodynamics Parameters

Measurement of
bioavailability
Pharmacokinetic methods ( indirect )
1. Blood analysis
2. Urinary excretion data
Pharmacodynamic methods ( direct )

1. Acute pharmacological response
2. Therapeutic response
18/11/2010 KLECOP, Nipani 44

Blood analysis
Plasma level time studies or The plasma concentration time
curve or blood level curve.
A direct relationship exists concentration of drug at the site of

action & concentration of drug in the plasma.
Serial blood samples are taken after drug administration &

analyzed for drug concentration.
A typical blood level curve obtained after oral administration of

drug.

Parameters determined
Pharmacokinetic parameters
Peak Plasma Concentration (Cmax)
Time of Peak concentration (tmax).
Area Under Curve (AUC)
Pharmacodynamics parameters
Minimum Effective Concentration (MEC) / Minimum
Inhibitory Concentration (MIC).
Maximum Safe Concentration (MSC) / Maximum Safe
Dose (MSD).
Duration of action
Onset of action.
Intensity of action.
AUC or Extent of absorption can be measured by 3
methods
1.Planimeter
Instrument for mechanically measuring the area
2. Cut & weigh method

AUC is cut & weighed on analytical balance. The weight
obtained is converted to proper unit by dividing it by the wt
of a unit area of same paper.
3. Trapezoidal method

3. Trapezoidal method
AUC = ( C1 + C2) (t2 t1) + (C2 + C3) (t3 t2) +.

(C n-1 + C n ) (tn tn-1 )
C = Concentration
t = time
subscript= sample number
AUC = Area Under Curve

Relative bioavailability
F rel = ( AUC) drug . (Dose) standard

(AUC) standard .(Dose) drug
Absolute bioavailability
Fab = (AUC)drug . (Dose) IV

(AUC)IV . (Dose) drug

From the following blood data obtained after the oral administration of 50mg of
drug A. calculate the AUC?
Time in hr Plasma drug con in mcg/ml

1 5.5
2 9.2
3 14.9
4 10.3
5 7.3
6 2.2
AUC
AUC == (5.5
(5.5+9.2)
+9.2) (2-1)
(2-1) + (9.2+14.9)
+ (9.2+14.9) (3-2)
(3-2) + + (14.9+10.3)
(14.9+10.3) (4-3) (1AUC(4-3)
=
(5.5
(10.3+
+9.2)7.1)(5-4) + (7.1 (3-2)
(2-1) + (9.2+14.9) +2.2)+ (6-5)
(14.9+10.3) (4-3) (10.3+ 7.1)(5-4) +
(7.1 +2.2) (6-5)
AUC = 45.35
AUC = 45.35mcg/ml
mcg/ml
hr hr
The AUC of a new sustained release diclofenac sodium

developed in the lab after giving in a dose of 100mg was
found to be 250.30 mcg/ml hr.The AUC of the standard
marketed sustained release tablets of the same at the
same dose was found to be 261.35 mcg/ml hr. what is
the the relative bioavailability of he same drug.
F rel = 250.30 X 100

261.35 X 100
= 0.9577 or 95.77%
The AUC of salbutamol sulphate from a 10 mg
IV dose was found to be 94.6mcg/ml hr.when
the same dose was given orally, the AUC was
found to be 60.5 mcg/ml hr. What is the
absolute bioavailability of the drug?
Fabs = 60.5 X 10
94.6 X 10
Fabs = 0.6395 or 63.95

Urinary excretion data
The method of determination bioavailability
provided that the active ingredient is excreted
unchanged in the significant quantity of urine.
The cumulative amount of active drug excreted in

urine is directly proportional to extent of systemic
drug absorption.
The rate of drug excretion is directly proportional

to rate of systemic drug absorption.
Advantages
Useful when there is lack of sufficiently sensitive analytical
techniques to measure concentration of drug in plasma.
Noninvasive method therefore better subject compliance.
Convenience of collecting urine samples in comparison to
drawing of blood periodically.
If any case the urine drug concentration is low, assaying of
larger sample volume is relatively more.
Direct measurement of bioavailability, both absolute &
relative is possible without the necessity of fitting the data
to the mathematical model.

Advantages

Advantages
Bioavailability is determined by.
F= (U ) oral . D IV
(U ) IV . D oral
U = Cumulative amt of unchanged drug excreted in

urine
D IV = IV dose
D oral = oral dose
F = absolute bioavailability

Advantages
When drug A was administered IV to a group of volunteers, 80%
of the 500mg dose was recovered unchanged in the urine. When
the same drug was administered to the same volunteers
orally.280 mg was recovered unchanged in urine. What is the
absolute bioavailability of Drug A following oral administration.
Absolute bioavailability = (cumulative amt.of drug excreted)sample

(cumulative amt.of drug excreted)IV
= 280
400
= 0.7 or 70%

Acute pharmacological response
Bioavailability can be determined from the acute

pharmacologic effect time curve as well as from dose
response graph.
DISADVANTAGE is that pharmacological response tends to

more variable & accurate correlation between the measured
response & drug available from the formulation is difficult.

Therapeutic response
This method is based on the observing the clinical response to a
drug formulation given to a patients suffering from disease for
which it is intended to be used.
Ex for anti inflammatory drugs, the reduction in the

inflammation is determined.
The major DRAWBACK is quantification of observed response

is too improper to allow for reasonable assessment of relative
bioavailability between two dosage forms of a same drug.

Rate of Absorption
AUC/dose gives an average extent of bioavailability.
The rate of absorption is usually also important

for the onset of drug action.
The time of peak plasma concentration is used

often as a measure of the rate of drug absorption.
The peak plasma concentration is also an

important parameter - for keeping the drug
concentration within the therapeutic window.
Absorption can be characterized by evaluating the absorption rate

constant Ka from the plasma concentration time data.
The method of Residuals
Also called as Feathering or peeling or stripping.
ASSUMPTIONS
Absorption & elimination process follows 1st order kinetics.
Absorption from the dosage form is complete.
Ka is at least five times larger than Ke
Kinetic model is
Ka
AG AB Kc AE


This technique is used to resolve a multiexponential
curve into its individual components.
For a drug that follows one compartment kinetics &
administered e.v, the concentration of drug in plasma is
expressed by
C= Ka F X0 [ e kEt e Kat ] 1
Vd ( Ka KE )
If Ka F X0 / Vd ( Ka kE ) = A, a hybrid constant then,

C=Ae kEt -A e Kat 2

During the elimination phase, when the absorption is
almost over, Ka > > KE & the value of second exponential e
Kat approaches zero whereas the 1st exponential e kEt
retains some finite value.at this time the equation is
C = A e kEt in log form

3
log C = log A KEt/ 2.303 4
Where C is the back extrapolated plasma concentration

value.
A plot of log C versus t yields a biexponential curve with a
terminal linear phase having slope KE/ 2.303.
Back extrapolation of this straight line to zero yields
y-intercept equal to log A.
Subtraction of true plasma concentration values that
is equation 2 from the extrapolated plasma
concentration values that is equation 3 yields a series
of residual concentration values Cr
( C - C ) = Cr = A e Kat ,
in log form the equation is :
log Cr = log A - Kat/ 2.303

A plot of logCr versus t yields a straight line with
slope Ka / 2.303 & y intercept log A.
Absorption half life can be computed from Ka using

the relation 0.693/Ka thus the method of residual
enables resolution of the biexponential plasma level
time curve into its exponential components.
The technique works best when the difference

between Ka & KE is large ( Ka >= 3)

Wagner Nelson Method
ASSUMPTIONS
The body behaves as a single homogenous compartment.
Drug elimination obeys 1st order kinetics.
DISADVANTAGES
The absorption & elimination processes can be quite similar &
still accurate determination of Ka can not be made.
The absorption process doesnt have to be 1st order.
The kinetics of absorption may be zero order, mixed order,
mixed zero order & 1st order or even more complex.
This method involves determination of Ka from percent
absorbed time plot & does not require the assumption of zero .

The amount of drug in the body X & the amt of drug eliminated
in the body XE thus :
XA = X + X E
If the amt of drug in the body is X = V.dCthe amt of drug

eliminated at any time t can be calculated as ..
XE = KE Vd ( AUC)to
Substitution of values of X & XE in above equation
XA = Vd C + KE Vd ( AUC)to
from this equation we can get the value for drug absorbed in to
the systemic circulation from time zero to


Thank you..
Cell No: 0091 974243100
E-mail: bknanjwade@yahoo.co.in

Pharmacokinetics Calculation

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Pharmacokinetics Calculations

Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

26-11-2010 KLECOP, Nipani 1

Elimination rate constant

26-11-2010 KLECOP, Nipani 2

26-11-2010 KLECOP, Nipani 3

26-11-2010 KLECOP, Nipani 4

ln y2 ln y1 ln2.0 ln 10.0 0.6931 2.3026

Therefore Ke = - slope = - (-0.2299/hr) = 0.2299/hr

26-11-2010 KLECOP, Nipani 5

26-11-2010 KLECOP, Nipani 6

Area from 0 to 7.0 hours

AUC0-7.0 by trapezoidal rule = 34.85 mcg.hr/ml

AUC0-7.0 by counting squares = 34.85 mcg.hr/ml

AUC0-7.0 by Cutting and Weighing = 34.85 mcg.hr/ml

26-11-2010 KLECOP, Nipani 7

Adding this value to AUC 0-7.0, we have

AUC0-infi = AUC0-7.0 + AUC7.0-

26-11-2010 KLECOP, Nipani 9

It shoes that a 250mg dose is administered

C = 1.5e-0.13t + 12.5 e1.3t.

Draw a schematic of the pharmacokinetic model,

In order to draw a schematic of the pharmacokinetic

26-11-2010 KLECOP, Nipani 12

ab (1.3/hr) ( o.13/hr) 0.169/hr

K12 = a + b K21 K10

K12 = 1.3 /hr + 0.13 /hr 0.2554 / hr 0.6617 / hr

26-11-2010 KLECOP, Nipani 13

(17.857 L) (0.5433 / hr+ 0.2554 / hr) 14.2624 L = 55.843 L

Vt = Vd Vc = 55.843 L 17.857 L = 37.986 L

(Vc) (K12) (17.857 L) (0.5433 / hr)

The first-order rate constant of transfer of the from the

26-11-2010 KLECOP, Nipani 15

26-11-2010 KLECOP, Nipani 16

were obtained when a 1 26.501

26-11-2010 KLECOP, Nipani 18

The biological half life (t1/2) is determined using the

Which upon rearrangement gives

26-11-2010 KLECOP, Nipani 23

26-11-2010 KLECOP, Nipani 24

The rate constant of absorption is obtained from the

26-11-2010 KLECOP, Nipani 25

Since 100% of the administstered dose was absorbed,

26-11-2010 KLECOP, Nipani 26

AUC = 503.597 mcg hr/ml 98.592 mcg hr /ml

= 405.005 mcg hr/ml

26-11-2010 KLECOP, Nipani 27

Calculate the time 1 26.501

26-11-2010 KLECOP, Nipani 29

ln 0.71 /hr ln 0.139 /hr

0.3425 (- 1.9733) 1.6308

26-11-2010 KLECOP, Nipani 30

Calculate the 1 26.501

26-11-2010 KLECOP, Nipani 31

C max = B (e-bt e-at)

C max = (70 mcg/ml) (e-(0.139/hr))(2.856 hr) e-(0.71/hr)(2.856hr))

C max = (70 mcg/ml) (0.623 0.1316)

C max = (70 mcg/ml) (0.5407)

26-11-2010 KLECOP, Nipani 32

were obtained when a 2 3.915

26-11-2010 KLECOP, Nipani 33

26-11-2010 KLECOP, Nipani 34