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Clinical Pharmacokinetics

Quantitative Aspects :
Time course of drug in the body.

Prof. H.Achmad Basori


Departemen Farmakologi
FK UNAIR

Pharmacokinetics in Clinical Practice, Greenblat &Shader


Pharmacokinetics made easy, Dinald J Birkett
Pharmacokinetics forn Non-Mathematical, DWA.Bourne

Receptor

Tissue
-protein
-fat

EFFECT

K+ Na+ Ca2+

I.V

Blood

Liberation

Specific barrier

FREE DRUG

Absorption
GI tract

PROTEIN
BOUND
DRUG

Renal

METABOLITE
-Aktif
-Tidak aktif

Enterohepatic
circulation
-Microsome
-Non microsome

Liver

Glomerular filtration
Tubular secretion
Passive reabsorption

BIOTRANSFORMATION

Plasma Level vs Time Plots


I.V
P.O, i.m

Pharmacokinetics (PK) and


pharmacodynamics (PD)

Plasma
Dose

Site
Concentration

PK

of
Effects
Action

PD
Sampling site

Thiopental concentration
(as percent of initial dose)

Biphasic Distribution Of Thiopental

100

blood

brain

muscle

50

0
1

10

100

minutes

adipose

1000

Primary Pharmacokinetics
Parameter
Clearance (Cl)
Half-lives (t )
Distribution Volumes (Vd)
Bioavailability ( F )
AUC

Secondary Pharmacokinetic Parameter


Vss, Css av, Css min, Css max, CL-h, CLR,dll

Kinetika eliminasi obat dari tubuh


ZERO-ORDER KINETICS
Process occurs at a constant rate. 1
Rate is independent of concentration. 2
FIRST-ORDER KINETICS
Process occurs at a decreasing rate. 1
Rate is proportional to concentration. 2

t Order Elimination
Fraksi obat yang dihilangkan dari tubuh
per satuan waktu adalah constan
Jumlah obat yang dieliminasi dari tubuh
per satuan waktu adalah tergantung
pada jumlah obat didalam tubuh
Hampir semua obat dieliminasi dari tubuh
menurut reaksi tingkat pertama ( first
order reaction)

Zero order
jumlah obat yang dieliminasi
persatuan waktu adalah konstan
(Theophylline, Aspirine, Phenytoin)

:First-order process
dC/dT = kC (constant fraction)

:Zero-order process
dC/dT = k (constant amount)

:Capacity limited process


; low C, first-order
high C, zero-order

Kinetika Obat Dalam


Tubuh
Zero Order
Kinetics
Rate = k
C = Co - kt
C vs. t graph
LINEAR

First Order
Kinetics
Rate = k C
C = Co e-kt
C vs. t graph tdk
linear, menurun
secara
. exponential
Log C vs. t graph
. linear

First order
ate of elimination depends
n plasma concentration

Zero Order
rate of elimination is constant
and independent of plasma
concentration

Linear kinetics
(most drugs)

Non-linear
kinetics
(e.g. phenytoin)
Rate of
eliminatn

Rate of
eliminatn

Blood drug conc

Blood drug conc

Linear

At steady state ...

Non-linear

Rate of
elim
=
Rate of
admin

Rate of
elim
=
Rate of
admin

Blood drug conc

Blood drug conc


Blood
drug
conc

Blood
drug
conc

Rate of admin

Rate of admin

First Order Elimination (Linier)

Plasma concentration

dC/dt C

DC/dt = k C
DC/dt = kC
Ct = C0 . e Kel t
lnCt = lnC0 Kel t
logCt = logC0 Kel t
2.3
y

a.x

Log Plasma Concentration

10000

First Order Elimination

1000
100
10
1

4
Time

lnCt = lnC0 Kel.t


logCt = logC0 - Kel
2.303
Ln = 2.3 log
Bila Ct = Co,
Kel.t = 0.693.

t1/2 = 0.693/Kel
t : the time for the plasma concentration to
reach half the original, i.e., the half-life of
Useful in estimating:
elimination.
- time to reach steady state concentration.
- time for plasma concentration to fall after dosing is
stopped.

HALF LIFE AND PERCENT OF


DRUG REMOVED
Number of
Percent of Drug
Percent of Drug
Half-lives Remaining
Removed
0
100
0
1
50
50
2
25
75
3
12.5
87.5
4
6.25
93.75
5
3.125
96.875

Half life and onset of action using


maintenance dose and no loading dose
Number of
Percent of final
Half-times
steady state concentration
0
0
1
50
2
75
3
87.5
4
93.75
5
96.875

Contoh : kalau diberikan dengan interval = t

Half life

hours

Lignocaine

steady state
8 hours

Valproate

24 hours

Digoxin

32

6 days

Digitoxin

161

28 days

:Penggunaan t1/2
1. t1/2 dapat digunakan untuk memprediksi berapa lama
obat dieliminasi dari plasma from plasma.

1.

Conc. (mg/L)

10

2.
50

7.5

4.

3.

5.

87.5
94 97
75
percent eliminated %

t1/2 = 2 hours

2.5

2.5

1.25

0.625

time (h)

10

2.t1/2 dapat vdigunakan untuk memprediksi berapa lama waktu


yang diperlukan dari mulai pemberian dosis sampai
mencapai kedaan tunak (steady state) pada pemberian dosis
ganda atau continuous i.v. infusion.

No. of t1/2
1
2
3
4
5

Concentration achieved
(% of steady conc.)
50
75
87.5
94
97

The time to reach steady state is ~5 t1/2s

Css
Concentration due to repeated
doses

Concentration due to a single dose

Intravenous infusion
Pada keadaan steady state (tunak)
rate of infusion = rate of elimination
= Css.Clearance
Css (plateau)
Cp

C = Css(1- e-kt)
Time to 90 % of Css = 4 t1/2
time

Fase ini ditentukan oleh


rate of elimination

Tingginya kadar tunak (plateau)


Ditentukan oleh rate of infusion

2X mg min-1
Cp

X mg min-1

time

.Table 1. Dose fractionation designs of an identical daily dose

Tam VH, Nikolaou M (2011) A Novel Approach to Pharmacodynamic Assessment of


Antimicrobial Agents: New Insights to Dosing Regimen Design. PLoS Comput Biol
7(1): e1001043. doi:10.1371/journal.pcbi.1001043
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1001043

1000 mg, bolus injection 10 menit

1000 mg, 3 h infusion

500 mg, 3 h infusion

MIC

Hubungan antara dosing rate dan

konsentrasi drug pada steady state


Ass: amount of drug in the body
Css: concentration in steady state
R: dosing rate
Dosing interval:
Pada steady state:
dosing rate = rate of elimination
R = A ss x k
A ss=C ss xVd
R = D/ = Css x Vd x k = Css x Vd x 0.693/t
C ss=1.44 x t1/2 x D/(Vd x )
A ss=1.44 x t1/2D/

Continuous repeating administration in


intravenous injection
Administration dose: D
Dosing interval:

:In steady state


dosing rate=rate of elimination
R=Assk
Ass=CssVd
R=D/ = CssVdk = CssVd0.693/t1/2
Css=1.44t1/2D/(Vd )
Ass=1.44t1/2D/

Selama continuous (infusion) atau continuous


intermittent dosing (oral dosing):
The steady-concentration tergantung pada kecepatan
pemberian dosis (the dose/dosing interval) dan
clearance.
Waktu yang diperlukan untuk mencapai steady-state
tergantung half-life dan tidak tergantung kecepatan
dosis dan clearance..

3. Berdasarkan hubungan antara t1/2 dengan dosing interval


) ,maka dapat digunakan untuk memprediksi derajad
accumulation dari obat didalam darah. Makin panjang t1/2
dan makin pendek , maka obat makin mengalami
accumulasi.
t1/2
Moderate accumulation during
dosing 2-times)
< t1/2 Significant accumulation during
dosing (> 2-times)
> t1/2 Insignificant accumulation during
dosing (< 2-times)

4. t1/2 (hubungan antara t1/2 dan interval t) dapat digunakan untuk


memprediksi derajad fluktuasi konsentrasi obat dalam interval
dosis .

t1/2 Css,min levels at steady state are aprox.


50% of Css,max. Moderate fluctuation.
< t1/2 Css,min levels at steady state are more
than 50% of Css,max. Small fluctuation.
> t1/2

Css,min levels at steady state are less


than 50% of Css,max. Wide fluctuation.

Multiple dosing
Pada pemberian dosis ganda kdr dalam
drh meningkat dengan cepat pada saat
pertama kdr dlm darah naik dgn cepat
lambat dan mencapai plateau
( kadar tunak),dimana :
rate of administration = rate of
elimination . steady state dicapai
Pada steady state:
Dose (Rate of Administration) = clearance x
plasma conc.

Dosing rate =Rate of elimination


(pada intermittent doses )
CSS max: maximum concentration of
steady state Peak C
Css min: minimum concentration of
steady state
Peak Time: It is a time achieving the
CSS max

The effect of loading dose immediate efficacy


LD

MD

Plasma Concentration

Single dose
Loading dose
Therapeutic
level

Repeated doses
Maintenance dose

Time

Css max

Css min

Css av

Multiple short i.v. infusions dari Amikacin:


kecepatan dosis tetap, tetapi interval berubah , t 1/2
1/2= 6 h

concentration in plasma
(mg/L)

50

300 mg, 8h

600 mg, 16h

40
30
20
10
0
0 12 24 36 48 60 72 84 96
time since start of dosing (h)

Multiple short i.v. infusions of amikacin:


the rate of dosing is constant but
interdose interval is changing, t1/2= 6 h

concentration in plasma
(mg/L)

300 mg, 8h

150 mg, 4h

50
40
30
20
10
0
0 12 24 36 48 60 72 84 96
time since start of dosing (h)

Loading dose
Diberikan pertama kali untuk mencapai Css
dengan cepat
Loading dose = Jumlah obat didalam tubuh
yang mencapai Css setelah diberikan
loading dose
Loading dose : dosis awal yang menaikkan
kadar obat dalam darah untuk mencapai
konsentrasi sasaran
Umumnya diberikan sebesar 2 x dosis
maintenance dan interval = t

C SS

Css=1.44t1/2D/(Vd )
Merubah interval dosis 0.5t1/2, t1/2,2t1/2, ;Dosis tetap,
, Css tetap
Tss berubah

Css=1.44t1/2D/(Vd )
Merubah dosis 2D, D, 0.5D; t1/2 tidak berubah,
Css berubah , Tss tidak berubah

Multiple dosing
Pada Steady State
amount administered = amount eliminated between doses

Cavss
Cp

Fase pada kurva ini ditentukan


oleh rate of elimination

time

Loading dose(s)
Loading dose = Cmax x Volume of distribution

Cp

time

Tetracycline t1/2 = 8 hours


500mg loading dose diikuti oleh 250mg setiap 8 hours

Cavss = F . Dose
Clearance. T
T = dosing interval

Cavss

Menurunkan dosis dan menurunkan interval


Cavss tetap, tetapi fluktuasi Cp berkurang

5. t1/2 dapat digunakan untuk memprediksi berapa waktu


yang diperlukan bila konsentrasi obat turun pada waktu
tertentu . Pada over dosis dan pengaturan dosis

t = t1/2 . ln(C1/C2) / 0.7

Plasma Level vs Time Plots

AUC = Jml Obat dalam tubuh

0
I.V

AUC = Dihitung menurut

Concentration

100

C.Dt = AUC

Trapezoidal Rule

0
Onset of action

Time

Area under the curve, AUC


C = C0 . e- k.t
monoexponential decay
AUC is an integral
AUC = Dose / (V . kel)
AUC = Dose / CL
CL= Dose / AUC (i.v.)
CL= F. Dose / AUC

The AUC value is very useful for calculating the amount of drug
which reaches the systemic circulation )the absolute bioavailability F(
after administration of different drug products.

PHARMACEUTICAL ALTERNATIVES
(the same API,diff chem form, (ester or salt), dosage form/strength)

PHARMACEUTICAL EQUIVALENTS
(The same API ,dosage form, route,identical in strength or conc)))

The same Bioavailability


WHO, 1998

No RCT

BIOEQUIVALENCE

(The same route, Pharm.Equiv, dosage form, labeled, GMP)

THERAPEUTIC EQUIVALENT
GENERIC SUBSTITUTION

BA Measurement
Bioavailability means the rate and extent to which the
`
active
ingredient or active moiety is absorbed from a drug
`
product and becomes available at the site of action
(FDA Guideline,2003).
Absolute bioavailability (F):

Cmax

AUCextravascular Doseint ravenous


F

AUCint ravenous Dose extravascular

Concentration

Ka

Relative bioavailability (Frel)

MBC
MIC

AUC

Tmax

Frel

AUC extravascular1 Doseextravascular 2

AUC extravascular 2 Doseextravascular1

Study Compound
Reference Compound

Time

Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER
Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic
Equivalence-Related Terms. Accessed September 29, 2003.

Non-linear
kinetics
(e.g. phenytoin)

Linear kinetics
(most drugs)

AUC

AUC

Rapid (bolus) i.v. injection and uniform mixing


of the amount administered throughout the volume
of total body water:

Vd=Dose/cplasma
Dose = cplasma . Vd

DIGOXIN DISTRIBUTION VOLUME


DOSE 750 g
Vd

536 L
C0
1.4 g/L

PLASMA VS. MYOCARDIAL DIGOXIN


LEVELS

PERIPHERAL VASCULAR EFFECTS

Single-compartment model
C
ka
Absorption

ke

Vd

Elimination

VOLUME OF DISTRIBUTION
Extracellular
Vascular

3L
4% BW

Extravascular

Intracellular

9L

28 L

13% BW

41% BW

Components of Total Body Water

Penentuan harga Vd
Pemberian obat secara intravena

Vd = Dose i.v /C0

Extrapolated estimate of C0

Log Conc

time

Apparent volume of distribution (Vd)

amount of drug in body


Vd
plasma drug concentrat ion
Vd =
VOLUME OF DISTRIBUTION FOR SOME DRUGS
Dose/C0
DRUG
cocaine
clonazepam
amitriptyline
amiodarone

Vd (L)
140
210
1050
~5000

Perhitungan Vd

mg/L

dosis 1000 mg suatu obat diberikan ke


pasien secara i.v. Kemudian kdr dlm darah
: ditentukan
100 100 mg/L hr 2
67 mg/L hr 4
45 mg/L hr 6
Vd=Dosis/Co
Co= 150 mg/L
Vd=1000/150 L= 6.7 L

10

4
Time (h)

: Volume compartments tubuh dalam hubungannya

dengan VDD

Total body water 0.6 L/kg BW


Intracellular water 0.4 L/kg BW
Extracellular water 0.2 L/kg BW
Plasma
0.04 L/kg BW
VDD 0.05 L/kg
the drug remains in the blood (heparine)
VDD 0.1-0.3 L/kg distribution from blood into extracellular
fluid (gentamicin - polar drugs).
VDD 0.6 L/kg
distribution from blood into intracelular
and extracellular fluid (methotrexate)
VDD >>0.6 L/kg distribution intracellularly and high
binding in tissues (amiodarone 350
L/kg)

Apparent Volume of Distribution )Vd(

Small Vd
Low tissue binding

Large Vd
Drug tightly bound

Vd beberapa obat obat


Drug

Liters/Kg

Liter/70 Kg

Chloroquine

94 250

6600 - 17500

Nortriptyline

21

1500

Digoxin

500

Lidocaine

1.7

120

Theophylline

0.5

35

Tolbutamide

0.11

Volume of distribution (Vd)


Lipid-insoluble drugs
Vd kecil
Distribusi obat hanya di plasma dan
cairan interstitial
Lipid-soluble drugs
Vd besar
Distribusi obat menuju semua
kompartemen
Vd melebihi volume cairan tubuh total
Obat terakumulasi diluar plasma
fat
Terikat kuat dengan jaringan

:Guna Vd
Vd dalam hubungannya dengan target concentration CT,. 1
:dapat digunakan menghitung loading dose DL
DL = VD . CT
2)Menentukan perkiraan jumlah obat dalam tubuh
Amount in the body = Vd . Cactual, measured
Untuk hemoperfusi. Biasanya obat dengan harga Vd besar,) 3
kurang efektif dari pada obat dengan Vd kecil
Perhitungan regimentasi dosis.4
Mengetahui distribusi obat, displacer, dll.5

LoadingL.dose
Dose= CP x VD

Contoh
EXAMPLE:
J.K.(TBW = 90 kg)was admitted to the ICU for
pneumonia caused by Gram-negative bacteria.
Calculate the loading dose of tobramycin for this patient
to achieve the target average concentration of 4 mg/l.
Tobramycin VD is 0.2 l/kg of TBW.
Loading Dose = ?
Loading Dose = 0.2 . TBW . Concentration Loading
Dose = 0.2 . 90 . 4 = 72 mg

Kriteria obat pendesak


(Displacer)
Asam organik
Afinitas terhadap albumin sangat kuat
Harga Vd kecil ( mendekati volume
plasma)
Kadar terapi dalam darah =
150mg/ml,BM:250
Kadar dalam plasma mendekati atau
lebih besar dari 0.06 mM

CONTOH INTERAKSI PENDESAKAN OBAT-PROTEIN


Obat pendesak

Obat yang
didesak

Efek farmakologi

Sulfonamide
Phenylbutazon
Salicylate

Tolbutamide

Hypoglycemic

Sulfinpyrazone
Warfarin
Oxyphenbutazon
Phenylbutazon

Hemorrhage

Sulfonamide
Salicylate

Methotraxate

Blood dyscrasia

Clofibrate
Mefenamic acid

Coumarin

Hypoprothrombin
aemia
/Hemorrhage

Reaksi Pendesakan obat


pada ikatannya dgn protein
plasma

Obat terikat kuat dgn protein-

Vd kecilMisalnya,. Aspirin warfarin


Experimental Drug A: 90% bound
10% free 11% free
Free drug concentration 10%
Experimental Drug B: 99% bound
1% free 2% free
Free drug concentration 100%

Clearance (CL)
Clearance Obat adalah ratio dari the rate of
elimination melalui semua rute thd the
.concentration of drug in plasma
CL = Kec. Rate of eliminination [mg / h ]
C in plasma [mg /L ]
Volume/Time [L/h] atau unit BB [l/h/kg]
Rate of eliminination = CL x C in plasma
(Amount / Unit of time)= (Volume / Unit of time) x C in
plasma

Unit: Volume/Time [L/h]

Kecepatan eliminasi = Kel x Jml Obat dlm tubuh


Kec eliminasi = CL x kadar dlm Plasma
Kel x Jml obatdlm tubuh = CL x Koncentrasi
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 = 0.693 x Vd/CL

Kecepatan Elim = Kel . D


Kec Elim = CL . C (vol/time)
Kel . D = CL. C

Vd = D/C
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 = 0.693 x Vd/CL
t1/2 = 0.693/Kel

half-life eliminasi dari suatu


obat dari tubuh
Tergantung pada pada clearance dan volume distribusi
t1/2 berbanding lurus dgn Vd
t1/2 berbanding terbalik dengan CL

t1/2 = 0.693 x Vd/CL

Rate of elimination
Elimination which follows first-order
kinetics: semi-log graph.
t 1/2 = 0.693/ kel
kel dihitung melalui the
linear-regression analysis

Pendekatan lain :
Clearance adalah volume plasma yang
secara sempurna dibersihkan dari obat per
unit waktu melui semua rute ( the liver, the
kidney).
Volume darah yang dibersihkan dari obat
.dari organ tertentu per satuan waktu
Clearance merupakan konsep yang lebih
fisiologik dari t 1/2 atau kel, karena
berdasarkan blood flow rate
Clearance bervariasi dengan berat

d Flow to organs
Lung
Adipose
Bone

Venous Blood

Brain

Arterial Blood

Heart
Kidney
Muscle
Skin
Liver
Portal
Vein
IV

Spleen
Gut
PO
100

Aliran darah menuju organ


5000 ml/minLungs
1350 ml/minLiver
1100 ml/minKidneys
750 ml/minMuscle
700 ml/minBrain
300 ml/minSkin
200 ml/min Fat

Clearance (CL)
Clearance has an additive character: it is the
sum of clearences in all eliminating organs
CL = CLRENAL + CLHEPATIC +CLpulmonary ...other
renal

+ nonrenal

Organ Clearance
Carterial

Cvenous
Organ of elimination

plasma flow

Elim. rate = Q(Carterial Cvenous)

(mass/time)

: E = Single pass extraction fraction


E = Elim. flux/ input flux = (Carterial Cvenous)/Carterial
Clearance Elim. rate/C (vol/time)

Clearance = EQ

Drug in Plasma

10g/m
l

Organs of
drug
elimination

500g
per min

<
10g/ml

CL = 500g/min
10g/ml

= 50ml/min

HEPATIC CLEARANCE
1. Mass Balance

Q x CA

Q x CV

Q(CA - CV)
Rate of Extraction

HEPATIC CLEARANCE
2. Mass Balance Normalized to Rate of Entry

1-E

E
Extraction Ratio

HEPATIC CLEARANCE
3. Mass Balance Normalized to CA

Q(1 E)

QxE
Clearance

Ingat CL = QE, maka


CL
=
Q
E
H
H
CLH = hepatic clearance
QH = hepatic blood flow
E = hepatic extraction ratio
QH - from 1.0 to 1.5 L/min
E ranges from 0 to 1

HEPATIC EXTRACTION RATIO OF


REPRESENTATIVE DRUGS
Low (<0.3)
Antipyrine
Diazepam
Phenylbutazone
Theophylline
Tolbutamide
Warfarin

High (>0.7)
Lidocaine
Meperidine
Propoxyphene
Propranolol
Verapamil

Intermediate: Quinidine

nical Aspect
Clearance Elim. flux/C
Eliminasi dari Unbound Cu (free fraction)
(metabolism, transport) Cu = fuC
)fu biasanya tidak diukur secara rutin(

Hepatic Clearance = EQ
High E (E>0.7), CL sensitive thd Q,
bukan fu Q menurun (Heart
failure, cirrhotic)
Metabolisme menurun
Low E (E<0.3) Q transit time
E
CL sensitive thd fu (CYP induction

BLOOD

B
LO
O
D

CA

OUT

CV
IN

Blood Flow = Q
ELIMINATED
Rate of Elimination = QCA QCV = Q(CA-CV)
Liver Clearance = Q(CA-CV)/CA = Q x EF

SIMILARLY FOR
OTHER ORGANS

Renal Clearance = UxV/Px

Total Body Clearance = CLliver + CLkidney + CLlungs + CLx

The principle of linear


pharmacokinetics
Rate of elimin. = CL .
Concentration

Nonlinear pharmacokinetics
Nonlinear pharmacokinetics: (capacitylimited, dose or concentration dependent,
saturable)
CL varies depending on the concentration
of a drug.
Rate of elimination = Vmax . C
Km + C
CL = Vmax

/Michaelis- Menten/
Km + C

ethanol, phenytoin, theofylline

Total Clearance (CLT or CL)


CL = CLR + CLH + nonrenal/nonhepatic clearance
:Harga CL dari dosis tunggal
Cl i.v. = Dose/AUC

: Oral Dose

CL p.o = F. Oral Dose/AUC


F = fraksi dose mencapai central pool
(plasma + jaringan dlm keseimbangan cepat dgn plasma

B
LO
O
D

CA

LIVER

BLOOD

OUT

CV

IN

Blood Flow = Q
ELIMINATED

Rate of Elimination = QCA QCV = Q(CA-CV)


Hepatic Clearance (Cl h) = Q(CA-CV)/CA=Q x E

Renal clearance
C x Cl r = U x V
C = plasma concentration,
Cl r = renal clearance,
U = urinary concentration,
V = urinary volume

Cl r = U x V/ C
CL t = Kel. Vd
CLt = CLh + Cl r

Renal Clearance )CLR(


.Net Elim. flux = filtration + secretion reabsorb

Net CLR = (urine exc. rate)/(mid-collection C)


)or use 24 hour urine collection and C(t)

Renal Filtration flux = GFR fuC


GFR CLcreat= 120 ml plasma water/minute
CLR << GFR fu significant reabsorption
CLR >> GFR fu significant secretion

Pharmacokinetic equations
Vd = dose/Co
Ke = 0.693/t 1/2
T 1/2 = 0.693/Ke
Cl = Vd x Ke
Cl = Dose /Co x Ke
Loading dose = Css x Vd
Maintenance dose = Css x Vd X Ke

Penderita asthma non-smoker, target conc Theophylline


10 mg/l Untuk mencegah serangan acute asma.
Harga tabel = Cl Theophylline =2.8 l/h/70 kg
Obat diberikan secara intra vena ( F=100 %)
p
Dosing rate = CL.TC
= 2.8 l/h/70 kg x 10 mg/l
= 28 mg / h / 70 kg
Kecepatan infusi pada penderita = 28 mg/h/70 kg

Bila serangan akut asma sudah ditanggulangi, klinisi


Ingin mempertahankan kadar Theophylline dalam darah
Dengan memberikan Theophyl SR p.o, setiap 12 jam.
Sesuai dengan tabel F p.o=0.96%.
Dosis pemeliharaan= Dosing rate/ F .Dosing interval
= 28 mg/h/0.96. 12 jam
= 350 mg

Linear (first-order) pharmacokinetics:


For most drugs, clearance is constant over the
plasma concentration range used in clinical
practice. Elimination is not saturable (noncapacity-limited) and the rate of drug elimination is
directly proporcionate to the concentration: