KOMPARTEMEN SATU TERBUKA:

PEMBERIAN INTRAVENA
FARMAKOKINETIK PERTEMUAN KE 4
One compartment

2
One compartment

3
More than one compartment

4
More than one compartment

5
Model Kompartemen Satu Terbuka
• Merupakan cara paling sederhana untuk
menggambarkan proses distribusi dan eliminasi
obat dalam tubuh
• Model ini menganggap obat masuk dapat masuk
dan meninggalkan tubuh (model terbuka) dan
tubuh berlaku seperti suatu kompartemen
tunggal yang seragam
• Rute pemakaian obat yang paling sederhana dari
pandangan pemodelan adalah injeksi intravena
bolus
 One compartment open model
• The simplest kinetic model that describes drug
disposition in the body is to consider that the drug is
injected all at once into a box, or compartment, and
that the drug distributes instantaneously and
homogenously throughout the compartment.

• Drug elimination also occurs from the compartment

immediately after injection.

7
 Fundamental parameters in one
compartment
• Apparent Volume of Distribution (Vd)
• Elimination rate constant (K)
• Elimination half life (t1/2)
• Clearance (Cl)

8
Apparent Volume of Distribution (Vd)
100 mg

C= 10 mg/L C= 1 mg/L
Vd= 10 L 9 Vd= 100 L
 Apparent Volume of Distribution (Vd)
• In general, drug equilibrates rapidly in the body. When plasma
or any other biologic compartment is sampled and analyzed
for drug content, the results are usually reported in units of
concentration instead of amount
• Each individual tissue in the body may contain a different
concentration of drug due to differences in drug affinity for
that tissue. Therefore, the amount of drug in a given location
can be related to its concentration by a proportionality
constant that reflects the volume of fluid the drug is dissolved
in
• The volume of distribution represents a volume that must be
considered in estimating the amount of drug in the body from
the concentration of drug found in the sampling compartment

10
The real Volume of Distribution has physiological
meaning and is related to body water

Total body water 42 L

Plasma Plasma volume 4 L

Interstitial Interstitial fluid volume 10 L

fluid

Intracellular Intracellular fluid volume 28 L

fluid

11
 Apparent Volume of Distribution
• Drugs which binds selectively to plasma proteins, e.g.
Warfarin have apparent volume of distribution smaller than
their real volume of distribution

• Drugs which binds selectively to extravascular tissues, e.g.

Chloroquines have apparent volume of distribution larger
than their real volume of distribution. The Vd of such drugs is
always greater than 42 L (Total body water)

12
 Apparent Volume of Distribution
• Lipid solubility of drug
• Degree of plasma protein binding
• Affinity for different tissue proteins
• Fat : lean body mass
• Disease like Congestive Heart Failure (CHF),
uremia, cirrhosis

13
 Volume Distribusi
• Vd dapat dinyatakan dalam volume atau dalam
istilah persen berat badan.
• Dalam persen berat badan 1 L volume di anggap
sama dengan berat 1 kg, jika di dapat Vd 3500 mL
untuk subjek dengan berat badan 70 kg , vd di
nyatakan dalam persen
• 35 kg : 70 kg x 100 =5 % berat badan
• Jika Vd yang diperoleh sangat besar, lebih dari
100%, obat di anggap berpusat dalam
kompartemen jaringan tertentu.
 Apparent Volume of Distribution:
Mathematics
• In order to determine the apparent volume of distribution of
a drug, it is necessary to have plasma/serum concentration
versus time data

dose X0
Vd  
initial conc. C0

15
Apparent volume of distribution estimation

1. Plot log(C) vs. time

2. Plot the best-fit line

3. Extrapolate to the Y-axis intercept (to estimate

initial concentration, C0)

4. Estimate Vd:
dose X0
Vd  
initial conc. C0
16
 Latihan Soal
• Seorang wanita dengan berat badan 50 kg
diberi obat antibakteri dengan dosis tunggal
intravena 6 mg/kg. sampel darah di ambil
pada berbagai waktu. Konsentrasi obat (Cp) di
tentukan dalam fraksi plasma dari masing2
cuplikan dan di peroleh data sebagai berikut
Dosis 300 mg, Vd= 10 L
T (jam) Cp ( Jumlah obat
mikrogram/
ml)
0.25 8.21 82.1 mg

0.5 7.87 78.7 mg

1 7.23 72.3 mg

3 5.15

6 3.09

12 1.11

18 0.40
 Pertanyaan
• Berapa harga Vd, k, T ½, Co untuk obat ini
• Obat antibakteri ini tidak efektif pada
konsentrasi plasma kurang dari 2 mikrogram
/mL. Berapa lama kerja obat ini?
• Berapa lama waktu yang diperlukan untuk
mengeliminasi obat sampai 99.9%
• Jika dosis antibakteri di duakalikan, apakah
akan terjadi kenaikan lama kerja aktivitas?
 1- Plot log(C) vs. time
7

6.8

6.6
Log (Conc)

6.4

6.2

5.8
0 1 2 3 4 5 6

Time
20
 2- Plot the best-fit line
7

6.8

6.6
Log (Conc)

6.4

6.2

5.8
0 1 2 3 4 5 6

Time
21
 3-Extrapolate to the Y-axis intercept (to
estimate C0)
7

6.8

6.6
Log (Conc)

6.4

C0
6.2

5.8
0 1 2 3 4 5 6

Time
22
 4-Estimate Vd
7

dose X0
6.8
Vd  
6.6
initial conc. C0
Log (Conc)

6.4

Log(C0)
6.2

5.8
0 1 2 3 4 5 6

Time
23
The Extent of Distribution and Vd in a 70 kg
Normal Man

% Body
Extent of Distribution
Vd, L Weight

5 7 Only in plasma
5-20 7-28 In extracellular fluids
20-40 28-56 In total body fluids.
In deep tissues; bound to
>40 >56
peripheral tissues
24
 Elimination rate constant (K)
• Elimination rate constant represents the fraction of
drug removed per unit of time

• K has a unit of reciprocal of time (e.g. minute-1, hour-

1, and day-1)

• With first-order elimination, the rate of elimination is

directly proportional to the serum drug
concentration

25
 Elimination rate constant estimation
1. Plot log(C) vs. time

2. Plot the best-fit line

3. Calculate the slope using two points on the

best-fit line
4. Estimate K:
K   Slope  2.303
26
 1- Plot log(C) vs. time
6.8

6.7

6.6
Log (Conc)

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
27
 2- Plot the best-fit line
6.8

6.7

6.6
Log (Conc)

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
28
 3- Calculate the slope using two points on
the best-fit lin
6.8

6.7
log( C1 )  log( C2 )
Slope 
t1  t 2
6.6
Log (Conc)

6.5

6.4

6.3
(Log(C1), t1)
6.2

6.1
(Log(C2), t2)

6
0 1 2 3 4 5 6

Time
29
 4- Estimate K
6.8

6.7
K   Slope  2.303
6.6
Log (Conc)

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
30
 Elimination half life (t1/2)
• The elimination half life is sometimes called
‘‘biological half-life’’ of a drug

• The elimination half life is defined as the time

(h, min, day, etc.) at which the mass (or
amount) of unchanged drug becomes half (or
50%) of the initial mass of drug

31
 Elimination half life (t1/2) estimation
• Two methods:
– From the value of K:
0.693
t1/ 2 
K
– Directly from Conc vs. time plot
• Select a concentration on the best fit line (C1)
• Look for the time that is needed to get to 50% of C1 
half-life

32
 Clearance (Cl)
• Clearance is a measure of the removal of drug from
the body

• Plasma drug concentrations are affected by the rate

at which drug is administered, the volume in which it
distributes, and its clearance

• A drug’s clearance and the volume of distribution

determine its half life

33
 Clearance (Cl)
• Clearance (expressed as volume/time) describes the removal of
drug from a volume of plasma in a given unit of time (drug loss
from the body)
• Clearance does not indicate the amount of drug being removed. It
indicates the volume of plasma (or blood) from which the drug is
completely removed, or cleared, in a given time period.
• Figures in the following two slides represent two ways of thinking
about drug clearance:
– In the first Figure, the amount of drug (the number of dots) decreases
but fills the same volume, resulting in a lower concentration
– Another way of viewing the same decrease would be to calculate the
volume that would be drug-free if the concentration were held
constant as resented in the second Figure

34
 Clearance (Cl)

the amount of drug (the number of dots)

decreases but fills the same volume,
resulting in a lower concentration

35
Clearance (Cl)

36
 Clearance (Cl)
• The most general definition of clearance is that it is ‘‘a
proportionality constant describing the relationship between
a substance’s rate of elimination (amount per unit time) at a
given time and its corresponding concentration in an
appropriate fluid at that time.’’

• Clearance can also be defined as ‘‘the hypothetical volume of

blood (plasma or serum) or other biological fluids from which
the drug is totally and irreversibly removed per unit time.’’

37
 Clearance (Cl) estimation
• For ALL LINEAR pharmacokinetics (including one
compartment) , clearance is calculated using:
dose
Cl 
AUC
where AUC is the area under the concentration curve
(it will be discussed later)

38
 Clearance (Cl) estimation
• For One compartment pharmacokinetics ,
clearance is calculated using:

Cl  K Vd

39
 Clearance (Cl)
• Drugs can be cleared from the body by
different pathways, or organs, including
hepatic biotransformation and renal and
biliary excretion. Total body clearance of a
drug is the sum of all the clearances by various
mechanisms.

Clt  Clr  Clh  Clother

(Cl t , Clr and Clh  total, renal, and hepatic Cl)
40
 Area Under the Conc. Time Curve
(AUC) calculation
• Two methods:
– Model dependent: can be used only for one
compartment IV bolus
– Model independent: Can be used for any drug
with any route of administration

41
 AUC calculation: Model dependent
• With one compartment model, first-order
elimination, and intravenous drug
administration, the AUC can be calculated
using:

Dose C0
AUC  
K Vd K

42
 AUC calculation: Model independent
1200

1000

800

600

400

200

0
0 2 4 6 8 10 12

43
 AUC calculation: Model independent
1200

1- Divide the area into different parts

based on the observed concentration
1000
points (parts 1-5)
800

600

400 1

200
2
3
4 5
0
0 2 4 6 8 10 12

44
 AUC calculation: Model independent
1200

1000
2- Calculate the area for each part of the
parts 1,2,3 and 4 (until the last observed
800 concentration) using trapezoidal rule

600

400 1

200
2
3
4 5
0
0 2 4 6 8 10 12

45
 Trapezoidal rule
(Trapezoid = ‫)شبه المنحرف‬

C1

C 2  C1
area   (t 2  t1 )
C2 2

where C = concentration
t = time

t1 t2

46
AUC calculation: Model independent

3- For part 5 (area between the last

observed concentration and infinity) use
the following equation:

C* C*
area 
K

47
 AUC calculation: Model independent
1200

1000
4- The total AUC (from zero to infinity) is the sum
of the areas of parts: 1,2,3,4, and 5

AUC 0  AUC1  AUC 2  AUC 3  AUC 4  AUC 5

800

600

400 1

200
2
3
4 5
0
0 2 4 6 8 10 12

48
 Fraction of the dose remaining
• Fraction of dose remainig (F = X(t)/X0) is given
by the following equation:

 K t
Amount at time t X 0  e  K t
F  e
dose X0
since t1/2= 0.693/k, the equation can be
represented as:
t
t
0.693
 1  t1 / 2
Fe t1 / 2
 
49 2
 Time to get to certain conc.
• Time to get to certain concentration (C*) is
given by:
 K t  K t C0
C*  C 0  e e 
C*
 C0 
K  t  ln  
 C *
 C0 
ln  
t  C * 
K
50
 Applications of one compartment model

• Case 1: Predicting Plasma Concentrations

• Case 2: Duration of Action

• Case 3:Value of a Dose to Give a Desired Initial

Plasma Concentration

51
 Case 1: Predicting Plasma Concentrations

• A 20-mg dose of a drug was administered as

an intravenous bolus injection. The drug has
the following pharmacokinetic parameters: k
= 0.1 h−1 and Vd = 20 L
1. Calculate the initial concentration (C0 )
2. Calculate the plasma concentration at 3 h

52
 Case 1: Predicting Plasma Concentrations

1. Calculate the initial concentration (C0 )

dose 20 mg
C0    1 mg/L
Vd 20 L
2. Calculate the plasma conc. at 3 h

 K t -(0.1)(3)
C  C0  e  1 e  0.74 mg/L

53
 Case 2: Duration of Action
• The duration of action of a drug may be
considered to be the length of time the
plasma concentration spends above the MEC.
Its determination is best illustrated by
example 2.

54
 Case 2: Duration of Action
• Continuing with the
drug used in Example 1,
if the therapeutic range
is between 5 and 0.3
mg/L, how long are the
plasma concentrations
in the therapeutic
range?

55
 Case 2: Duration of Action
• As indicated in the diagram (previous slide) C0
=1 mg/L. Thus, at time zero the plasma
concentration is in the therapeutic range. The
plasma concentration will remain therapeutic
until it falls to the MEC (0.3 mg/L). At what
time does this occur?

 C0 
ln  
 C *   1 
t  ln   / 0.1  12.0 hr
K 56
 0.3 
Case 3: Value of a Dose to Give a Desired Initial
Plasma Concentration
• Continuing with the drug used in Examples 1
and 2, If the initial Cp of 1 mg/L is
unsatisfactory, Calculate a dose to provide an
initial plasma concentration of 5 mg/L.

dose
C0  dose  C0 Vd
Vd
mg
dose  5  20 L  100 mg
L
57
Examples

58
 Example 1
• Ten mg metoclopramide was administered
intravenously to a 72 kg patient. The minimum
plasma concentration required to cause
significant enhancement of gastric emptying is
50 ng/mL. The following plasma
concentrations were observed after analysis of
the specimen.

59
 Example 1

Time (hr) Conc. (ng/ml)

1 90.0
2 68.0
4 40.0
6 21.5
8 12.0
10 7.0

60
 Example 1
• Calculate the biological half-life of the drug
elimination (t½), the overall elimination rate
constant (K), the volume (Vd), the coefficient
of distribution and the duration of action (td)
and clearence (Cl)

61
 Example 1
2.5

2
y = -0.1243x + 2.0832
R2 = 0.9995
log (Conc)

1.5

0.5

0
0 2 4 6 8 10 12
time 62
(hr)
 Example 1
• The elimination rate constant can be obtained
from the slope:

K  Slope  2.303
1
 (0.1243)  (2.303)  0.286 hr
• Another way to calculate the slope is using:

log(C1) - log(C2)
Slope 
t1 - t2
63
 Example 1
• Another way to calculate the slope (if you do not
have the ability to do regression) is using:

log(C1) - log(C2)
Slope 
t1 - t2
where (C1,t1) and (C2,t2) are two different conc. time
points

• It is important to note that the first method for

calculating the slope is more accurate
64
 Example 1
• Calculating the slope using the second method:

log(40) - log(21.5)
Slope   -0.13481
4-6
• Note that the value of the slope is similar to the
value estimated using the first method (-0.1243)

65
 Example 1
• the biological half-life of the drug elimination
(t½):
0.693 0.693
t 0.5    2.42 hr
K 0.286
• The volume of distribution (Vd):
dose 10 10
Vd   2.0832 
C0 10 121.12
mg 10 6 ng L
 0.083   3  83 L
ng/ml mg 10 ml
66
 Example 1
Intercept = log (C0)

2.5
C0= 10intecept

2
y = -0.1243x + 2.0832
R2 = 0.9995
log (Conc)

1.5

1
y = -0.1243x + 2.0832
R2 = 0.9995

0.5

0
0 2 4 6 8 10 12
time (hr) 67
 Example 1
• the coefficient of distribution = Vd/wt
=83 L/ 72 kg= 1.15 L/kg

• the duration of action (td). td is the time

needed for the conc. To get to 50 ng/ml :

 C0   121.12 
ln   ln  
t  C *    50   3.1 hr
K 0.286
68
 Example 2
• An adult male patient was given the first dose of an antibiotic at
6:00 AM. At 12:00 noon the plasma level of the drug was
measured and reported as 5 µg/ml. The drug is known to follow
the one compartment model with a half-life of 6 hours. The
recommended dosage regimen of this drug is 250 mg q.i.d. the
minimum inhibitory concentration is 3 µg/ml. Calculate the
following:
– Apparent volume of distribution
– Expected plasma concentration at 10 AM.
– Duration of action of the first dose
– Total body clearance
– Fraction of the dose in the body 5 hours after the injection
– Total amount in the body 5 hours after the injection
– Cumulative amount eliminated 5 hours after the injection
– Total amount in the body immediately after injection of a second dose at 12:00
noon
– Duration of action of first dose only if dose administered at 6:00 AM was 500 mg.

69
 Example 2
• Elimination rate constant:
K  0.693  0.693  0.116 hr 1
t 0.5 6
• Initial concentration:
– The conc. at 12:00 noon (6 hrs after the
first dose) is 5 µg/ml:
 k t
C (t  5)  C0  e
C (t  5) 5
 C0   k t
 0.1166  10 ug/ml
e e 71
 Example 2
• Apparent volume of distribution:
C(t=6hrs)= 5 ug/ml. Since the half life is 6 hrs, C0 = 10
ug/ml.
X0 250 mg
VD    25000 ml  25 L
C0 μg 10 mg
-3
10 
ml μg
• Expected plasma concentration at 10 AM

K  0.693 /t 0.5  0.693 / 6  0.1155 hr -1

C(t  4)  C0  e  Kt  6.3 μg/ml

72
 Example 2
• Duration of action of the first dose
 C0   10 
ln   ln  
t   C *  3  10.42 hr
K 0.1155
• Total body clearance
Cl  K  VD  2.89 L/hr

• Fraction of the dose in the body 5 hours after the

injection
5
1 6
F     0.56
2 73
 Example 2
• Total amount in the body 5 hours after the injection
= (0.56)(250 mg) = 140 mg

• Cumulative amount eliminated 5 hours after the

injection = dose – amount in the body = 250 – 140
= 110 mg

• Total amount in the body immediately after

injection of a second dose at 12:00 noon
Total amount = amount from the first dose + amount
from the second dose = 125 + 250 = 375 mg
74
 Example 2
• Duration of action of first dose only if dose
administered at 6:00 AM was 500 mg
t d  10.42 hr  6 hr  16.42 hrs

• Note that 6 hrs (one t0.5) is needed for the

amount in the body to decline from 500 mg to
250 mg

75
 Example 3
• The therapeutic range of a drug is 20-200 mg/L. After
an intravenous bolus injection of 1.0 gm followed by
regression analysis of the concentration of the drug
in plasma (in units of mg/L) versus time (in hours),
the following linear equation was obtained

log Cp  2  0.1t
• Calculate the following
– Duration of action
– Total body clearance
– Rate of elimination at 2 hours

76
 Example 3
• From the equation:
log Cp  2  0.1t  log( C0 )  slope  t
The following were estimated:
C0  10 2  100 mg/L

K  Slope  2.303  (0.1)  (2.303)  0.23 hr 1

X 0 1000 mg
VD    10 L
C 0 100 mg/L
77
 Example 3
• Duration of action:
 C0   100 
ln   ln  
td   C *    20   7 hr
K 0.23
• Total body clearance= K∙Vd=(0.23)(10) =2.3 L/hr
• Rate of elimination at 2 hours:
• Elimination rate = Cl*C(t=2) = 2.3*63 =145 mg/hr

log(Cp(t  2))  2  (0.1)(2)  1.8

 Cp(t  2)  101.8  63 mg/L
78