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BIOFARMASETIKA

DAN
FARMAKOKINETIKA

DEWA AYU PUTU SATRYA DEWI


INSTITUT ILMU KESEHATAN MEDIKA PERSADA BALI
OUTLINE
How important to study this lecture?

Model Kompartemen

Model Kompartemen Satu Terbuka

Volume Distribusi

Konstanta Eliminasi & T ½ Eliminasi

Klirens

AUC

Diskusi

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How Important?

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Model Kompartemen
Kompartemen 1 Kompartemen 2
log (C)

Time
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Kompartemen Satu Terbuka

 The one-compartment open model offers the


simplest way to describe the process of drug
distribution and elimination in the body.

 This model assumes that the drug can enter or


leave the body (ie, the model is "open"), and the
body acts like a single, uniform compartment.

 The simplest route of drug administration from a


modeling perspective is a rapid intravenous
injection (IV bolus).
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Kompartemen Satu Terbuka

 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.
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Kompartemen Satu Terbuka

IV bolus Elimination process


administration Drug amount in the
Body (DB, VD) Elimination rate
constant (K)

 DB : Obat dalam tubuh


 VD : Volume Distribusi (jumlah dosis/Do dan konsentrasi
obat dalam plasma/Cp
 K : Tetapan laju eliminasi yang menentukan laju penurunan
konsentrasi obat selama waktu tertentu

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Kompartemen Satu Terbuka

D  K t
C e
Vd
Drug Conc (C)

C= concentration
D= dose
Vd: Volume of distribution
K: elimination rate constant
t: time
Time

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Kompartemen Satu Terbuka

How to distinguish one comp?


Plotting log(C) vs. time
yields a straight line
log (C)

Time

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Volume Distribusi

 Volume distribusi menyatakan suatu


volume yang harus diperhitungkan dalam
memperkirakan jumlah obat dalam suatu
tubuh dari konsentrasi obat yang
ditemukan dalam kompartemen sampel.
 Vd = Volume obat terlarut

 DB= VD.Cp VD = DB/C

 kt 0
Log Cp =  log C
2,3 p

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Volume Distribusi

 VD bergantung pada Cp0, untuk dosis tertentu ,


Cp0 dalam tubuh sangat kecil yang disebabkan
oleh konsentrasi obat dalam jaringan perifer dan
organ
 Cp0 yang kecil akan menghasilkan VD yang besar
 VD besar terpusat pada ekstravaskuler >
intravaskuler
 Jika suatu obat terikat pada protein plasma dalam
jumlah yang besar atau tinggal dalam vaskuler,
maka Cp0 tinggi dan VD kecil
 Ikatan obat dengan protein plasma atau jaringan
perifer secara bermakna akan mempengaruhi VD

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Volume Distribusi

• In order to determine the apparent volume of distribution of


a drug, it is necessary to have plasma/serum concentration
versus time data

dose DB 0
Vd  
initial conc. Cp0

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Volume Distribusi

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 DB 0
Vd  
initial conc. Cp0
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Volume Distribusi

7 1- Plot log(C) vs. time


6.8

6.6
Log (Conc)

6.4

6.2

5.8
0 1 2 3 4 5 6

Time
14
Volume Distribusi

7 2- Plot the best-fit line


6.8

6.6
Log (Conc)

6.4

6.2

5.8
0 1 2 3 4 5 6

Time
15
Volume Distribusi

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
16
Volume Distribusi

7
4-Estimate Vd
dose DB 0
6.8
Vd  
6.6
initial conc. Cp0
Log (Conc)

6.4

Log(C0)
6.2

5.8
0 1 2 3 4 5 6

Time
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Konstanta Eliminasi

IV bolus Drug amount in the Elimination process


administration
Body (DB, VD) Elimination rate
constant (K)

 Kosntanta eliminasi sebagian besar mengikuti orde 1 (jumlah


atau konsentrasi obat)
 Satuan waktu-1 ( misal jam-1 atai 1/jam)
 K = Km (laju metabolisme) + Ke (laju eksresi)

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Konstanta Eliminasi

Elimination rate constant estimation


1. Plot log(C) vs. time

1. Plot the best-fit line

2. Calculate the slope using two points on the


best-fit line
3. Estimate K:
K   Slope  2.303
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Konstanta Eliminasi

6.8
1- Plot log(C) vs. time
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
20
Konstanta Eliminasi

6.8
2- Plot the best-fit line
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
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Konstanta Eliminasi

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
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Konstanta Eliminasi
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
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T ½ Eliminasi

• 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

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T ½ Eliminasi

• 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

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Klirens (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

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Klirens (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

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Klirens (Cl)

the amount of drug (the number of dots)


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

28
Klirens (Cl)

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Klirens (Cl)

• Pendekatan Massa
Dosis = 100 mg
Jumlah tereliminasi/menit
Volume cairan = 10 ml
= 10 mg/menit
Kons. = 10 mg/ml

• Pendekatan Klirens (volume)


Dosis = 100 mg
Volume tereliminasi/menit
Volume cairan = 10 ml
= 1 mg/menit
Kons. = 10 mg/ml

• Pendekatan Fraksi
Dosis = 100 mg Fraksi tereliminasi/menit
Volume cairan = 10 ml = 1 mg/menit
Kons. = 10 mg/ml = 1/10 per menit

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Klirens (Cl)

2. Pendekatan Klirens (volume)


Dosis = 100 mg
Volume tereliminasi/menit
Volume cairan = 10 ml
= 1 mg/menit
Kons. = 10 mg/ml

• Klirens merupakan suatu konsep yang


menyatakan “laju pembersihan obat” dalam
istilah volume larutan obat yang dibersihkan
per satuan waktu.

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Klirens (Cl)

• 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 next slide)

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Klirens (Cl)

• For One compartment pharmacokinetics ,


clearance is calculated using:

Cl  K Vd

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Area Under the Cons. (AUC)

• 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

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Area Under the Cons. (AUC)

• With one compartment model, first-order


elimination, and intravenous drug
administration, the AUC can be calculated
using:

Dose C0
AUC  
K Vd K

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Area Under the Cons. (AUC)

1200
AUC calculation: Model independent
1000

800

600

400

200

0
0 2 4 6 8 10 12

36
Area Under the Cons. (AUC)

1200
AUC calculation: Model independent
1000 1- Divide the area into different parts
based on the observed concentration
800 points (parts 1-5)

600

400 1

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

37
Area Under the Cons. (AUC)

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

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Area Under the Cons. (AUC)

Trapezoidal rule
C1

C 2  C1
area   (t 2  t1 )
C2 2

where C = concentration
t = time

t1 t2

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Area Under the Cons. (AUC)

AUC calculation: Model independent


3- For part 5 (area between the last
observed concentration and infinity) use
the following equation:
C*
C*
area 
K

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Area Under the Cons. (AUC)

1200
AUC calculation: Model independent
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

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DISKUSI 1

1. Suatu dosis tunggal IV dari suatu antibiotika baru diberikan


kepada seorang wanita dengan berat 50 kg dengan dosis 20
mg/kg. Sampel urine dan darah diambil secara berkala dan
ditentukan kadar obat induk. Didapat data sebagai berikut :
Waktu (jam) Cp (mcg/mL) Du (mg)
0.25 4.2 160
0.50 3.5 140
1.0 2.5 200
2.0 1.25 250
4.0 0.31 188
6.0 0.08 46

Hitunglah nilai konstanta eliminasi dan T ½ eliminasi !


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DISKUSI 2

2. Seorang sukarelawan dengan berat badan 70 kg


diberi antibiotik dosis intravena dan konsentrasinya
dalam serum ditentukan pada 2 jam dan 5 jam
setelah pemberian. Konsentrasinya berturut-turut
1,2 dan 0,3 microgram/mL. Berapa t ½ biologik
obat ini, bila dianggap kinetika eliminasi mengikuti
orde kesatu?

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Jawaban Diskusi 2

t (jam) C ( microgram/mL)
2 1,2
5 0,3

kt 0 0,693
Log Cp =   log C t 1/2 =
2,3 p k

Log Cp =  k (3) 0,693


 log 1,2 t 1/2 =
2,3 0,462
k = 0,462 jam-1
t 1/2 = 1,5 jam

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DISKUSI 3
3. Seorang wanita dengan BB 50 kg diberi obat antibakteria
dengan dosis tunggal intravena 6 mg/kg. Sampel darah
diambil pada berbagai jarak waktu. Konsentrasi obat (Cp)
ditentukan dalam fraksi plasma dari masing-masing cuplikan
darah dan diperoleh data sebagai berikut :
t (jam) Cp (microgram/mL)
0.25 8.21
0.50 7.87
1.00 7.23
3.00 5.15
6.00 3.09
12.00 1.11
18.00 0.40

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DISKUSI 3

a. Berapa harga Vd, k, dan T ½ untuk obat ini?


b. Obat antibakteri ini tidak efektif pada konsentrasi plasma
kurang dari 2 microgram/mL. berapa lama kerja obat ini?
c. Berapa lama waktu yang diperlukan untuk mengeliminasi
obat sampai 99,9%?
d. Jika dosis antibakteri diduakalikan, apakah akan terjadi
kenaikan lama kerja aktivitasnya?

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JAWABAN DISKUSI 3

• Dosis (IV Bolus) = 6 mg/kg X 50 kg = 300 mg

Dosis 300mg
a. Vd =   35,7 L
Cp0 8,4mg / L

t ½ (dari grafik) = 4 jam


k= 0,693  0,173 jam  1
4

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JAWABAN DISKUSI 3

b. Cp0= 8,4 microgram/mL


Cp= 2 microgram/mL
k= 0,173jam-1
kt 0
Log Cp =   log C
2,3 p
0,713t
Log 2 =   log 8,4
2,3
t= 8,29 jam

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JAWABAN DISKUSI 3

C. (1) Mendekati 10 x T ½
t = 10(4) = 40 ja,
(2) Cp0 = 8,4 mcg/mL
dengan 0,1% obat tertinggal
Cp = 0,001 (8,4 mcg/mL) = 0,0084 mcg/mL
k= 0,173 jam-1
log 0,0084 =  0,713t  log 8,4
t = 39,9 jam 2,3

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JAWABAN DISKUSI 3

D. Jika dosis diduakalikan maka Cp0 akan dua kali, k dan


t ½ tetap, maka :
Cp0 = 16,8 mcg/mL
Cp = 2 mcg/mL
k = 0,173 jam-1
log 2 =  0,713t  log 16,8
2,3

t = 12,3 jam

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