FARMAKOKINETIKA

KLINIK
 PHARMACOKINETICS

CAN BE DEFINED AS THE

CHARACTERIZATION OF TRANSPORT
PROCESSES OF DRUGS AND OTHER
XENOBIOTICS IN THE BODY
•KNOWLEDGE ABOUT THE HUMAN PHARMACOKINETICS
OF A DRUG AND THE APPLICATION OF THE
PHARMACOKINETIC PRINCIPLES IS
NECESSARY TO UNDERSTAND FULLY FEATURES OF THE
DRUG AND THE INTERINDIVIDUAL DIFFERENCES IN
THERAPEUTIC AND TOXIC EFFECTS.

•CLINICAL PHARMACOKINETICS
FARMAKOKINETIKA KLINIK

MENGAPA ?

UNTUK MENCAPAI TERAPI OPTIMAL

– PERLU “DRUG OF CHOICE”, MENYANGKUT KEPUTUSAN TENTANG :

• Akurasi Diagnosis dari penyakit
• Kondisi Klinis Pasien harus Tercatat/terpantau
• Managemen terapi :
– How Much ? MEC - MTC
– How Often ? MEC - MTC
– How Long ? Cost - Benefit
 PUSTAKA
Shargel, L & Yu. A.BC 2005, Aplied Biopharmaceutics and
Pharmacokinetics, Fifth Ed. Appleton, Century -
Crofts.
Winter, E.W., 1994., Basic Clinical Pharmacokinetics, 3rd Ed.
Applied in Therapeutics Inc.,Vancouver WA.

Breimer, D.D.1992. Pharmacokinetics and New Drug

Delivery, Advanced Course in Pharmaceutical
Sciences, UGM Yogyakarta.
Rowland, M. and Tozer, TN. 1995. Clinical
Pharmacokinetics, Concepts and Applications,
Third Ed., Sea and Fehger, UK.
 PENGGUNAAN RASIONAL

• TEPAT INDIKASI
• TEPAT PENDERITA
• TEPAT OBAT
• TEPAT DOSIS, RUTE, SAAT
PEMBERIAN & LAMA
PEMBERIAN
• WASPADA TERHADAP E.S.O.
 KESALAHAN PADA CUSTOMER
(TENAGA DOKTER )
 PENULISAN RESEP BERLEBIHAN
(MELAMPAUI BATAS) (EXTRAVAGANT
PRESCRIBING)
 PENULISAN RESEP TERLALU BANYAK (OVER
PRESCRIBING)
 PENULISAN RESEP YANG SALAH
(INCORRECT PRESCRIBING)
 PENULISAN RESEP GANDA (MULTIPLE
PRESCRIBING)
 PENULISAN RESEP YANG KURANG (UNDER
PRESCRIBING)
 OBAT

PELANGGAN
(CUSTOMER)

KONSUMEN
(PASIEN)
Pharmacokinetics Pharmacodynamics

Dosage Drug at Site

Effect
Regimen of Action

Figure Relationship of pharmacokinetics and pharmacodynamics

 Concentration
Plasma Drug

Pharmacologic Response
Figure When pharmacologic effects relate to plasma drug concentrations,
the latter can be used to predict the former
 Drug in Drug in
Blood Tissue

Sample Removed for Drug

Concentration Determination

Figure Blood is the fluid most often sampled for drug concentration
determination
Concentration of Drug

High
in Plasma

Kidney
Plasma
Receptor
Low
Concentration of Drug Time
in Tissues

Figure Relationship of plasma Figure Drug concentration

to tissue drug concentration versus time
 Cell Signal
(2nd Messenger)
Altered
Receptor Cellular
Expression Event

Gene Regulation

Regulation of Protein Production

CELL
Drug

Receptor

Figure Relationship of drug effect to drug concentration at the

receptor site
 Maximun Effect (Emax)

100 100

Effect (%)
Effect (%)

50 50

EC50

5 10 20 10 100
Plasma Drug Concrentration (mg/L) Plasma Drug Concrentration (mg/L)
(log scale)

Figure Relationship of effect (as a percentage of maximal effect) to

drug concentration at the receptor
 Later Dose
First Dose
100

Effect (%)

50

Plasma Drug Concrentration (log scale)

Figure Demonstration of tolerance to drug effect with repeated dosing

THERAPEUTIC DRUG MONITORING “TDM”

- MEMILIH OBAT
- MERANCANG ATURAN DOSIS
- MENILAI RESPON PENDERITA
- MENENTUKAN PERLUNYA PENGUKURAN KADAR OBAT
DALAM DARAH
- PENETAPAN KADAR OBAT DALAM DARAH
- MELAKUKAN PENILAIAN SECARA FARMAKOKINETIKA
- MENYESUAIKAN KEMBALI ATURAN DOSIS
- MEMANTAU KADAR OBAT DI DALAM DARAH
- MENGANJURKAN ADANYA PERSAYARATAN KHUSUS
(JIKA PERLU)
 Activity-Toxicity Pharmacokinetics
Therapeutic window Absorption
Side effects Distribution
Toxicity Metabolism
Concentration-response Excretion
relationship

Dosage
Regimen

Clinical Factors
Management of therapy
Multiple drug therapy
Other Factors
Route of administration,
State of patient
Dosage form, Tolerance-
Age, weight Pharmacogenetics-

Convenience of regimen ,Condition being Drug interactions , Cost

Compliance of patient treated, Existence of

other disease states
• PEMILIHAN OBAT
– INDIKASI TERAPETIK SAMA –ELIMINASI DAN
METABOLISME BERBEDA
– DIDASARKAN PADA DIGNOSIS YANG TEPAT
– FARMAKODINAMIK DAN KADAR TERAPETIK
– F.KINETIKA OBAT
– KONDISI PATO-FISIOLOGIS
– RIWAYAT OENGOBATAN SEBELUMNYA
– TERAPI TUNGGAL / GANDA
– ALERGI / KEPEKAAN
– DAFTAR OBAT ESENSIAL
– HARGA
– KENYAMANAN & KEPATUHAN
 RANCANGAN ATURAN DOSIS

ACTIVITY –TOXICITY
TERAPEUTIC WINDOW
SIDE EFFECT
TOXICITY
CONCENTRATIONS-RESPONS RELATIONSHIPS
PHARMACOKINETICS
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION
 CLINICAL FACTORS

STATE OF PATIENT :
AGE, WEIGHT,GENDER, NUTRITIONAL,
CONDITION BEING TREATED, RENAL DYSFUNCTION,
LIVER DEASESE, CONGESTIVE HEART FAILURE
EXISTENCE OF OTHER DESEASE STATES

MANAJEMEN OF THERAPY :
MULTIPLE DRUG THERAPY
CONVENIENCE OF THERAPY
COMPLIANCE OF PATIENT
 OTHER FACTORS

- ROUTE OF ADMINISTRARION
- DOSAGE FORM
- TOLERANCE
- PHARMACOGENETICS
- DRUG INTERACTIONS : ENVIROMENTAL
FACTORS (SMOKING)
- CELL TARGET (RECEPTOR) SENSITIVITY
- COST
 A diagnosis is made

A drug is selected

Dosage schedule is
designed to reach a
target plasma
concentration
If dosage adjustment

Drug is administered
necessary

Patient assessments Drug concentrations

are performed are determined

A pharmacokinetic
model is applied and
clinical judgement is
used
Figure Process for reaching dosage decisions with therapeutic drug
monitoring
PENILAIAN RESPON PENDERITA

RESPON POSITIF : TERUS

RESPON KURANG :
-EVALUASI DOSIS & INTERVAL ; INTERAKSI
-EVALUASI FARMAKODINAMIK
-KEPATUHAN

RESPON NEGATIF : STOP

 PENGUKURAN KADAR OBAT
DI DALAM DARAH
- PERLU PERTIMBANGAN YANG TELITI UNTUK MEMUTUSKAN
PENGUKURAN (TIDAK EFEKTIF / TOKSIK/ALERGI)
- SERUM TUNGGAL KURANG EFEKTIF.
- PERHATIAN PADA : Cav , Cmaks, Cmin.
- WAKTU PENGAMBILAN CUPLIKAN
- BESARNYA (VOLUME) CUPLIKAN
- BIAYA
- KENYAMANAN PASIEN
- MANFAAT YANG DIPEROLEH
PEMANTAUAN KONSENTRASI OBAT DI DALAM DARAH
DIPERLUKAN JIKA :

“ EFEK TERAPETIK DAN TOKSIK TIDAK DAPAT DENGAN MUDAH

DIAMATI SECARA KLINIS”

HAL INI DILAKUKAN UNTUK OBAT-OBAT SBB. :

 OBAT DENGAN “NARROW THERAPEUTIC RATIO” (Cardiac

Glycosides).

 OBAT YANG MENUNJUKKAN VARIABILITAS KADAR DALAM

DARAH ANTAR INDIVIDU YANG SUKAR DI PREDIKSI PADA
DOSIS YANG SAMA (Amitriptilin)

 KEADAAN KLINIK PENDERITA :

GAGAL GINJAL, PENYAKIT LIVER, GANGGUAN SISTEM
PENCERNAAN, TERAPI GANDA (RESIKO TINGGI KARENA
INTERAKSI), TERAPI KRONIK (KEPATUHAN PASIEN),
PASIEN YANG DICURIGAI TERJADI INTOKSIKASI
 Toxicity
Concentration
Plasma Drug
Increasing

Optimal Therapeutic
Therapy Range

Sub-therapeutic

Figure Plasma drug concentration relates to toxic and therapeutic effects

 30

25
Highest Plasma Drug
Concentration

20

15 Mean

10

Dose (mg) 100

Figure Variability in plasma drug concentration among subjects

given the same drug dose
 PENILAIAN FARMAKOKINETIK
TERHADAP HASIL PENGUKURAN KADAR OBAT :

- KADAR TOTAL (BEBAS & TERIKAT)

- PARAMETER NORMAL
- RENTANG TERAPETIK
- KONS. PUNCAK, PALUNG, AVARAGE
 HASIL : LEBIH RENDAH, LEBIH TINGGI, SAMA

LEBIH RENDAH:

- KEPATUHAN PASIEN
- KESALAHAN ATURAN DOSIS
- SALAH PRODUK OBAT (PELEPASAN KENDALI SEBAGAI GANTI
PELEPASAN SEGERA)
- BIOAVAILABILITAS YANG JELEK
- ELIMINASI CEPAT
- PENINGKATAN VOL DISTRIBUSI
- JADWAL PENGAMBILAN CUPLIKAN
 LEBIH TINGGI :

- KEPATUHAN PASIEN
- KESALAHAN ATURAN DOSIS
- SALAH PRODUK OBAT
- BIOAVAILABILITAS CEPAT
- ELIMINASI LAMBAT (GAGAL GINJAL)
- VOLUME DISTRIBUSI LEBIH RENDAH

KONSENTRASI BENAR, TAPI TIDAK

ADA RESPON F.KOLOGI:

- KEPEKAAN BERUBAH
- INTERAKSI OBAT-RESEPTOR
 DRUG ASSAY

SPESIFISITAS : TIDAK TERCAMPUR METABOLIT, OBAT LAIN,

ENDOGENOUS & EXOGENOUS FACTORS.
SENSITIVITAS : KADAR MINIMUM YANG DAPAT DITETAPKAN (LIMIT
OF DETECTION)
LINEARITAS : LINEAR DNG. METODA LAIN YANG LAZIM, LINEAR
ANTARA KADAR DAN SIGNAL.
KETEPATAN / PRESISI : REPRODUKTABILITAS (SD, C.V.INTER DAN
INTRA ASSAY)
KETELITIAN : AKURASI (RECOVERY)
STABILITAS : BAIK STANDARD ATAU CUPLIKAN.
 Indicated
Drug Route Dosage Regimen
Use
Theophylline Relief of Oral 160 milligrams
asthma every 6 hours
Digoxin Ameliora- Oral 1.5-2 milligrams
tion of initially over 24
congestive hours, thereafter
cardiac 0.25-0.5 milligram
failure once a day
Oxytocin Induction Intravenous 0.2-4
and main- milliunits/minuts
tenance of infusion
labor
Morphine Relief of Intramuscul 10 milligrams when
sulfate severe pain ar needed Not
Oral recommended
because of reduced
effectiveness
PHARMACOKINETICS PHARMACODYNAMICS
Dosage Plasma Site Of
Action Effects
Regimen Conc.

REGIMEN B THERAPEUTIC FAILLURE

REGIMEN A
THERAPEUTIC SUCCESS

THERAPEUTIC FAILLURE

TIME
Drug Dose Compartment

Elimination
Figure Simple compartmental model
 Central Examples of
Compartment Peripheral
Compartment

Heart

Fat Tissue
Liver

Lungs Muscle
Tissue

Kidney

Cerebrospinal
Blood Fluid

Figure Typical organ groups for central and peripheral compartments

 distribution

Tissue Receptor
Effect
compartment

G.I. plasma
tract
protein

kidney liver metabolism

excretion

elimination
PHYSIOLOGICAL PRIMARY SECUNDARY
VARIABLES PHARM.KINETIC PHARM.KINETIC
PARAMETERS PARAMETERS

- bloodflow - volume of - elimination rate

- protein binding distribution (Vd) constant
- kidney function - clearance, CL - elimination half-life
- enzyme activity - Absorption rate - oral bioavailability
of the liver Constant, Ka
(- gastric emptying time)
TO ADMINISTER DRUGS OPTIMALLY, THEREFORE,
KNOWLEDGE IS NEEDED NOT ONLY OF THE MECHANISM OF
DRUG ABSORPTION, DISTRIBUTION, AND ELIMINATION BUT
ALSO OF KINETICS OF THESE PROCESSES, THAT IS,
“PHARAMACOKINETICS”.
THE APPLICATION OF PHARAMACOKINETIC PRINCIPLES TO
THE THERAPEUTIC MANAGEMENT OF PATIENTS IS “CLINICAL
PHARMACOKINETICS”
Plasma Drug Concentration

Time
 KEAKURATAN FARMAKOKINETIKA
SEBAGAI “POWER TOOL” DALAM TERAPI
TERGANTUNG PADA 3 HAL :

 METODA ANALISA OBAT DI DALAM

CAIRAN HAYATI
 METODA FARMAKOKINETIKA YANG
DIGUNAKAN
 HUBUNGAN FARMAKOKINETIKA-
FARMAKODINAMIKA (LOG.DOSE - RESPON).
 V Max
Km = Michaelis - Menten
Constant
dAb ½ V Max
dt

Km C
dAb V max
 xC
Jika C <<< Km dt Km  C Jika C >>> Km
Maka Maka
dAb V max
 xC dAb dAb
dt Km  CL.C  V max
V max  mg / h dt dt

Km  mg / L dAb Saturasi Transport

CL  /C
dt
V max mg L
 x
Km H mg
 “ FIRST ORDER KINETICS “ ELIMINATION

Q.CA Q.Cv

Q ( CA- C V )

Q(CA  C V ) CA  CV
CL  E
CA CA
CL = Q . E

Cl = Clearance ( L / H )
Q = Blood Flow ( L / H )
E = Extraction Ratio
dAb
CL  /C
dt
“Ratio Between Rate of Elimination and concentration“
 CLEARANCE

HIGH CLEARANCE DRUGS LOW CLEARANCE DRUGS

BLOODFLOW

BLOODFLOW

E
Do V

Co

CL

dAb
dt
= CL . C (1)

dC CL
dt
= . C (2)
V

dC = k . C (3)
dt
In which k = elimination rate constant ( h -1 )
Ab= Amount of Drug in the Body; V=Vol. of
Distr.;C=Drug Conc.
Integration of equation 3 results in

C = Co e - kt
C ln C

slope = - k

Time Time
 Elimination half-life

C = Co e - kt
at t ½ C = 0.5 Co

0.5 xCo = Co e - kt ½
0.5 = e - kt ½
ln 0.5 = - k . t ½

t½ = 0.693 / k
 Cp o

I.V. BOLUS

Cp = Cp o e - Kt
C Dosis i.v
Vd = Cp o

(K
T

A Cp = Ae -t + Be -ßt
Dosis i.v
B Vc = Cp o
C
K12 + K21
Vdss = . Vc
K21

(α (

T
 A=B=Cpo Cp = B.e -Kt - A.e - Kat
F . D i.v
Vd :
Cpo
C
K

Ka

T
Cpo
Cp = B.e - βt + A.e - t - Cpo.e - Kat
A

β
Ka α
T
 INFUSI INTRAVENA
Kadar Tunak ( C ss ) = Cp
~

Setelah Pemberian infusi

T --> Cp akan mencapai keadaan
“ Plateau “ = Konsentrasi
2R Tunak
C

T
PROSENTASE (%) WAKTU
KADAR TUNAK YANG DIBUTUHKAN

90 3,32 X T1/2
95 4,32 X T1/2
99 6,65 X T1/2
 Cp = Konsentrasi obat di plasma
R
Cp  (1  e  Kt ) R
(mg/L)
= Laju infusi ( mg / jam )
Vd.K
Vd = Vol. Distribusi ( L )
K = Tetapan laju diminasi ( jam-1 )

Infus
dihentikan

K
Slope =
2,303
T
 R
Cp ~
(1  e  Κ(~) )
Vd.Κ
Karena e  K(~) mendekati nol

R
Cp ~ 
Vd.K

Contoh :
Suatu antibiotik Vd = 10 L & K = 0,2 Jam -1
Konsentrasi tunak dalam plasma yang dikehendaki = 10 µg / ml
berapa laju infusi yang harus diberikan ?
R = Cp Vd . K
= 10 µg / ml x 10.000 ml x 0,2 jam-1
= 20 mg / jam
 DOSIS MUATAN
(LOADING DOSE = INITIAL DOSE)
 R
DL 
Κ
DL  Vd.C ~
p
 CONTOH :
Soal :
SUATU XENOBIOTIKA AKAN DIBERIKAN SECARA
INFUSI INTRA-VENA. UNTUK MENCAPAI KADAR
2 g/mL DENGAN SEGERA PERLU DOSIS MUATAN.

Diket :
K = 0,1 /JAM
Vd = 10 L.

Pertanyaan :
1. BERAPA DOSIS MUATAN (DL) YANG HARUS
DIBERIKAN UNTUK MENGAWALI INFUS TERSEBUT?
2. HITUNG PULA KECEPATAN INFUSI YANG HARUS
DIBERIKAN.
 R
a. DL >
K

R
b. DL =
K
a
KTM R
c. DL <
K

d. DL = O ( tanpa DL )
b Cp

Cp

T
 PENGATURAN DOSIS BERGANDA

– MEMPERPANJANG AKTIVITAS TERAPETIK PADA KADAR

PLASMA EFEKTIF.

– PRINSIP SUPER POSISI :

DOSIS OBAT SEBELUMNYA TIDAK MEMPENGARUHI
KINETIKA OBAT BERIKUTNYA.

– OVERLAY / SUPERIMPOSE :
KADAR DARAH KE-N AKAN OVERLAY PADA KADAR
KE- N-1
 t2

Pada keadaan tunak  AUC t1  t 2 (  Cpdt)

t1
t2

Dosis tunggal  AUC 03 (  Cpdt)

t1

C
AUC
t1-t2

AUC 0-tak terhingga

T t1 t2
 D D D D D D D D

T T T T T T T

Steady State
ss
C max

C max4 Cavss

C max3 ss
C min
Concentration

C max2

C (0)
C min3

C min2
C min1

Time Tn Tn+1
 Do
Dmax =
1- f

FDo
Dmax = k 
Cop
Cmax =
1 - e -k 
D
f = Do = e -k  Co e-k 
p
Cmin =1 - e -k 

FDo
Cav = V k 
D
 Do 1  e  nkλ  kt
Cpn    kλ 
.e
VD  1  e 
Jika n besar dan t = λ
Do  1 
Cpmax 
VD 1  e kλ 

MULTIPLE ORAL REGIMEN

Fk a Do  1  e  nkaλ   kat  1  e  nkaλ   kat 

Cp   e  
 nkaλ 
e 
 nkaλ 
VD (k  k a )  1  e  1 e  
 FDo
~
C av
VD .k.λ

FDo
C 
~
av Jika ka >>>>>>> k
C1T λ
k a FDo  1  kt  1  kat 
C 
~
  kaλ 
e   kaλ 
e 
VD (k  k a )  1  e 1 e
p
  

FDo  1 
C ~
  kλ 
VD  1  e 
max
2.3 ka
t max  log
FDo  1  k ka  k k
C ~
   kλ 
e
VD  1  e 
min
( single dose )
 1  k a (1  e ) 
 kλ
tmax  ln   kλ 
k a  k  k(1  e ) 
( Multiple Dose )
LOADING DOSE
~
VD Cav
DL 
(S)(F)
20
t1/2<
t1/2 = 6 hours
 = 20 hours
15

10

0 20 40 60 80
Time ( Hours )
 t1/2=
t1/2 = 6 hours
 = 6 hours

20 19,37 19,69
18,75
17,5

15

10
9,69
9,37
8,75
7,5

0 24 48 72
Time ( Hours )
 t1/2>
t1/2 = 24 hours
 = 6 hours

20

10 Accumulation

0 24 48 72
Time ( Hours )
• INJEKSI INTRA-VENA BERGANDA
• CONTOH :
– SEORANG PENDERITA MENERIMA ANTIBIOTIK (T1/2
= 3 JAM; Vd = 20 L; SATU KOMPARTEMEN) DOSIS 1000
MG SETIAP 6 JAM. TENTUKAN HARGA Cp maks, Cp
min, dan Cav.OBAT TSB.

• PEMBERIAN ORAL BERGANDA :

• CONTOH :
– SEORANG PENDERITA DEWASA LAKI-LAKI (46 TH, 81
KG), MENDAPAT TETRASIKLLIN HCL ORAL DOSIS 250
MG SETIAP 8 JAM SELAMA 2 MINGGU (F=0,75;
Vd=1,5L/KG.BB; T1/2 = 10 JAM; Ka = 0,9 /JAM). HITUNG
Cmaks, Cmin, dan Cav.PADA KEADAAN STEADY STATE.
Figure 18-1. Nomogram for
evaluation of endogenous
creatinine clearance. To use the
nomogram, connect with a ruler the
patient's weight on the second line
from the left with the patient's age
on the fourth line. Note the point of
intersection on R and keep the rule
there. Turn the right part of the
ruler to the appropriate serum
creatinine value and the left side
will indicate the clearance in
mL/min. (From Kampmann &
Siersback-Nielsen 1974, with
permission.)
Figure 18-3. Nomogram for
rapid evaluation of endo-
genous creatinine clearance
(Clcr) in pediatric patients
(aged 6-12 yr). To predict Clcr,
connect the child's Scr (serum
creatinine) and Ht (height)
with a ruler and read the Clcr :
where the ruler intersects the
center line. (From Taub &
Johnson 1980, with
permission.)
 Nomograf ini
menggambarkan
perubahan pada
prosentase tetapan
laju eliminasi
normal (ordinat
kiri) dan
konsekuensi
kenaikan
geometrik waktu-
paruh eliminasi
(ordinat kanan)
sebagai suatu
fungsi dari klirens
kreatinin. Obat-
obat yang
berhubungan
dengan slop
individual
diberikan dalam
Tabel 16-2 (dari
KN= tetapan kecep eliminasi normal Welling C, 1976,
dengan izin. 8)
KU= tetapan kecep eliminasi uremia

1. TETAPKAN KELOMPOK GOL. OBAT PADA TABEL 16-2

2. DAPATKAN KU/KN PADA TITIK YANG SESUAI DENGAN CLCR
3. TENTUKAN HARGA KU
4. SESUAIKAN DOSIS DENGAN KU BARU
 TABEL 16.2. TETAPAN LAJU ELIMINASI UNTUK BERBAGAI OBAT *

Kelompok Obat KN (jam-I) Knr(jam-l) KnrlKN (%)

A Minosikiina 0,04 0,04 100,0
Rifampisin 0,25 0,25 100,0
Lidokaina 0,39 0,36 92,3
Digitoksin 0,114 0,10 87,7
B Doksisiklina 0,037 0,031 83,8 * KN adalah
Klortetrasiklina 0,12 0,095 79,2
C Klindamisin 0,16 0,12 75,0 untuk penderia
Kioramfenikol
Proponolol
0,26
0,22
0,19
0,16
73,1
72,8
dengan fungsi
Eritromisin 0,39 0,28 71,8 ginjal normal;
D Trimetoprim 0,054 0,031 57,4
Isoniazid (cepat) 0,53 0,30 56,6 Knr adalah untuk
Isoniazid (Iambat) 0,23 0,13 56,5 pendenta
E Dikioksasilin 1,20 0,60 50,0
Sulfadiazina 0,069 0,032 46,4 dengan
Suifametoksazol 0,084 0,037 44,0
F Nafsilin 1,26 0,54 42,8
kerusakan ginjal
Klorpropamida 0,020 0,008 40,0 berat ; dan
Linkomisin 0,15 0,06 40,0
G Kolistimetat 0,154 0,054 35,1 Knr/KN % =
Oksasilin 1,73 0,58 33,6
Digoksin 0,021 0,007 33,3 prosen eliminasi
H Tetrasikiina 0,120 0,033 27,5 normal pada
Kloksasilin 1,21 0,31 25,6
Oksitetrasiklina 0;075 0,014 18,7 penderita
I Amoksisilin 0,70 0,10 14,3
Methisilin 1,40 0,19 13,6
dengan
J Tikarsilin 0,58 0,066 11,4 kerusakan ginjal
Penisilin G 1,24 0,13 10,5
Ampisilin 0,53 0,05 9,4 berat. (dari
Karbenisilina 0,55 0,054 9,1
K Cefazolin 0,32 0,02 6,2
Welling C,
Cefaloridina 0,51 0,03 5,9 1976, dengan
Cefalotin 1,20 0,06 5,0
Gentamisin 0,30 0,015 5,0 izin. 8)
L Flusitosina 0,18 0,007 3,9
Kanarnisin 0,28 0,01 3,6
Vankomisin 0,12 0,004 3,3
Tobramisin 0,32 0,010 3,1
Cefaleksin 1,54 0,032 2,1
The Methode by Jellife is as follows. For female
patients, one would use 90% of the CLcr obtained for
males.
98  (age  20)
Clcr  (18.14)
Ccr
The methode by Cockroft and Gault (1976; Eq. 18.15) is also
used to estimate creatinine clearence from serum creatinine
concentration. This methode does include both age and weight
of the patient.
Males :
[(140  age (yr)] x body weight (kg) (18.15)
Clcr 
72 (Ccr)
Female :
for female patients use 85% of the Clcr value obtained
in males
Example :
The Bioavailability of digoxin tablet (lanoxin)
is 0,7 (F=0,7)

Amount of drug absorbed

= (F) (dose)
on Reaching Systemic Circ.

If the dose of lanoxin tablet is 250 µg

Amount of drug absorbed = (0,7)x(250 µg)
= 175 µg
Bioequivalent ( Be) :
Amount of new Dosage form
= 100%
Amount of drug Absorbed
From Current Dosage Form

The New Dosage Form equivalent to the

Current Dosage form (standard dosage form)

In term of pharmacokinetics :

Area under the curve (AUC)

of new dosage form
= 100%
Area under the curve (AUC)
of standard dosage form
Example :
If a patient who has been receiving digoxin
250 µg in the tablet dosage form ( 175 ug
absorbed, F = 0,7), needs to receive elixin in
stead, an equivalent dose of elixin would be
calculated by using the F of elixin dosage
form ( F = 0,77) 175 µg
Dose elixin =
0,77
= 227 µg ( less then digoxin
tablet dosage form) or
calculated from = 0,70: 0,77 x
250 ug = 227 ug
CHEMICAL FORM (S)

The chemical form of a drug also be

considered when evaluating bioavailability

The fraction of chemical form is “S”

Ammount of Drug Absorbed = (S) (F) X Dose

 METODA PENILAIAN BA
 1. DATA PLASMA :
 AUC

 Cmax

 Tmax

 2. DATA URIN
 Du kum
 dDu/dt
 Tinf (waktu mencapai Du kum maks.)
 3. EFEK FARMAKOLOGI AKUT
 4. PENGAMATAN KLINIK
3. EFEK FARMAKOLOGI :
BILA PENGUKURAN KADAR OBAT TIDAK DPT DILKUKAN
ATAU TIDAK REPRODUKTIF

MISAL
- EFEK PADA DIAMETER PUPIL
- KECEPATAN DENYUT JANTUNG
- BESARNYA TEKANAN DARAH

► “SYARAT: KURVA EFEK VS WAKTU PERLU

FREKWENSI YANG CUKUP DAN DURASI 3 X
T1/2”
 4. PENGAMATAN KLINIS

 KLINISI DAPAT MENGAMATI KEGAGALAN

TERAPI (RESPON KURANG, ATAU ADA
GEJALA TOKSIK)
 MISAL : T ½ THEOPHYLLIN PD DIET
TINGGI KARBOHIDRAT 18,1 JAM > T1/2
THEOP. PD DIET NORMAL 6,76 JAM
(FELDMAN dkk.,1982 :”Interaction
between Nutrition and Theophyllin
metabolism”. Ther.Drug Monit.,4, 69-67)