Kuliah MKDU-3

7/25/2019 Kuliah MKDU-3

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Clinical PharmacokineticsQuantitative Aspects :

Time course of drug in the body.

Prof. H.Achmad Basori

epartemen !armakologi

!" #$A%&


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Pharmacokinetics in Clinical Practice, Greenblat &Shader

Pharmacokinetics made easy, Dinald J BirkettPharmacokinetics forn Non-Mathematical, DW!Bo"rne


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'% tract

(iver

Blood

")$a)Ca*)

AA

%.+(iberation

Absorption

B%,T&A$-!,&AT%,$

!&// 'P&,T/%$

B,#$

'

/TAB,(%T/

Tissue

-protein-fat

&enal

-pecific barrier

&eceptor/!!/CT

Enterohepatic

circulation 'lomerular filtration

Tubular secretion

Passive reabsorption0icrosome

0$on microsome

0Aktif

0Tidak aktif


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Plasma Level vs Time Plots

#!$

P!%, i!m


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Plasma Site Concen- of

tration Action

Eects

P PD

Pharmacokinetics (PK) and

pharmacodynamics (PD)

Dose

Sam'lin( site


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Th

iopentalco

ncentration

(as

percentof

initialdose)

100

0

0

min!tes

1 10 100 1000

"lood

"rainm!scle adipose

Biphasic #istri"!tion $f Thiopental


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inetika eliminasi obat dari t"b"h

)*+%-%+D*+ #N*#CS

!Process occ"rs at a constant rate

.!+ate is inde'endent of concentration

/#+S-%+D*+ #N*#CS

!Process occ"rs at a decreasin( rate.!+ate is 'ro'ortional to concentration


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Order Elimination

Fraksi obat yang dihilangkan dari tbh

!er satan "akt adalah constan#mlah obat yang dieliminasi dari tbh!er satan "akt adalah tergantng!ada $mlah obat didalam tbh

%am!ir sema obat dieliminasi dari tbhmenrt reaksi tingkat !ertama & 'rstorder reaction(

)ero order$mlah obat yang dieliminasi!ersatan "akt adalah konstan

)*heo!hylline, +s!irine, Phenytoin(


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1inetika Obat 2alam*bh,ero $rderinetics

Rate k

C Co - kt

C vs3 t gra!hL45E+R

*irst $rderinetics

Rate k CC Coe

-kt

C vs3 t gra!h

tdklinear, menrnsecara

ex!onential.

Log C vs3 t gra!hlinear.

%i


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)ero %rder/irst order

te of elimination de'ends

'lasma concentration

rate of elimination is constant

and inde'endent of 'lasma

concentration


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&ate of

eliminat1n

&ate of

eliminat1n

Blood drug conc Blood drug conc

Linear kinetics(most drugs)

Non-linear

kinetics(e.g. phenytoin)

A d


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&ate of

elim

2

&ate of

admin

&ate of

elim

2

&ate of

admin

Blood

drug

conc

Blood drug conc

Blood

drug

conc

&ate of admin &ate of admin

Blood drug conc

(inear $on0linear At steady state ...


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Time

(ogPlasmaConcentration

7 . 8 9 : ;

7

77

777

7777

/irst %rder *limination


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lnCt2 lnC34 "el.t

t / the time for the plasma concentration toreach half the oriinal i2e2 the half-life ofelimination2

t134 5 026783el

Bila Ct 5 Co

el2t 5 026782

+sef!l in estimatin/

- time to reach stead% state concentration2

- time for plasma concentration to fall after dosin isstopped2

loCt 5 loC0 - el

42808

Ln 5 428 lo


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%+LF L4FE +52 PERCE5* OF

2R67 RE8OVE29!m"er of Percent of #r! Percent of #r!'alf-lives :emainin :emoved

0 100 01 0 04 4


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%al/ li/e and onset o/ action singmaintenance dose and no loading dose

9!m"er of Percent of ?nal'alf-times stead% state concentration

0 01 04


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5i(nocaine . < ho"rs

$al'roate ; .9 ho"rs

Di(o3in 8. ; days

Di(ito3in ; .< days

=alf life ho"rs steady state

Contoh > kala" diberikan den(an inter?al 1 t @

P t


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Pen(("naan tA.>7. t76* dapat digunakan untuk memprediksi berapa lama

obat dieliminasi dari plasma from plasma.

0

2.5

5

7.5

10

0 2 4 6 8 10

time 4h6

Conc!4m

(A56

5

2.5

1.250.625

t1/2= 2 hours

1. 2.

3. 4.

percent eliminate

5.

50 75 87.5 !4 !7


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

yang diperlukan dari mulai pemberian dosis sampai

mencapai kedaan tunak (steady state) pada pemberian dosisganda atau continuous i.v. inusion.

No! of tA. Concentration achie?ed

4 of steady conc!6 :7

. :

8


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The time to reach steady state is 89 t76*1s


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Concentration due to a single dose

Concentration due to repeated

doses

The time to reach steady state is 89 t76* s

Css


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Pada &eadaan stead% state (t!na&)rate of inf!sion 5 rate of elimination

5 Css2Clearance

Css 4'latea"6

ime to 7 of Css 1 9 tA.

@ntraveno!s inf!sion

C'

time

C 1 Css4- e-kt6


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E m( min-

.E m( min-

/ase ini ditent"kan oleh

rate of eliminationin((inya kadar t"nak 4'latea"6

Ditent"kan oleh rate of inf"sion

C'

time


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able ! Dose fractionation desi(ns of an identical daily dose!

Tam +H $ikolaou ;*377< A $ovel Approach to Pharmacodynamic Assessment of

Antimicrobial Agents: $e= %nsights to osing &egimen esign. P(o- Comput Biol

>;[email protected]?5http:66===.ploscompbiol.org6article6info:doi673.75>[email protected]?5
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1001043http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1001043


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00 m 8 h inf!sion

1000 m 8 h inf!sion

1000 m "ol!s inection 10 menit

M#C


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%bngan antara dosing rate dan


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%bngan antara dosing rate dan

konsentrasi drg !ada steady state+ss9 amont o/ drg in the body

Css9 concentration in steady state

R9 dosing rate

#osin interval/

Pada stead% state/

dosin rate 5 rate of elimination

: 5 A ss &

A ss5C ss d: 5 #3 5 Css d & 5 Css d 026783t

C ss512>> t134 #3(d )

A ss512>> t134#3


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Continos re!eating administration in

intravenos in$ection+dministration dose9 2

2osing interval9 :

4n steady state:dosing raterate o/ elimination

R+ss;k

+ssCss;Vd

R2: Css;Vd;k Css;Vd;?t@ACss512>>Dt134#3(dD )

+ss@3BB;t@A2:


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-elama continuous ;infusion< atau continuous

intermittent dosing ;oral dosing


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

memprediksi dera!ad luktuasi konsentrasi obat dalam interval

dosis .

t1/2 "ss#min levels at steady state are apro$.

%&' o "ss#ma$. oderate luctuation.

< t1/2"ss#min levels at steady state are more

than %&' o "ss#ma$. mall luctuation.

> t1/2 "ss#min levels at steady state are less than %&' o "ss#ma$. *ide luctuation.


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2osing rate Rate o/ elimination

)!ada intermittent doses(

CSSmax9 maximm concentration o/

steady state

Peak C

Css min9 minimm concentration o/

steady state

Peak *ime9 4t is a time achieving the

CSSmax


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-i l d


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Time

PlasmaConcentration

&epeated doses 4

aintenance dose

Therapeutic

level

-ingle dose 4

(oading dose


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ultiple short i.v. inusions dari -mikacinultiple short i.v. inusions dari -mikacin


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u t p e s o t us o s da ac

kecepatan dosis tetap# tetapi interval berubah # t1/2 0 h

p

kecepatan dosis tetap# tetapi interval berubah # t1/2 0 h

0

10

20

30

4050

0 12 24 36 48 60 72 84 !6

time since start of dosin( 4h6

concentrationin

'lasma

4m(A56

300 m&( 8h 600 m&( 16h

*ultiple short i ' in+usions o+ ami$acin:*ultiple short i.'. in+usions o+ ami$acin:


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*ultiple short i.'. in+usions o+ ami$acin:

the rate o+ osin& is constant %ut

interose inter'al is chan&in& t1/2

= 6 h

*ultiple short i.'. in+usions o+ ami$acin:

the rate o+ osin& is constant %ut

interose inter'al is chan&in& t1/2

= 6 h

0

10

20

3040

50

0 12 24 36 48 60 72 84 !6

time since start of dosin( 4h6

concentrationin'lasma

4m(A56

300 m&( 8h 150 m&( 4h


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C

C SS

Css@3BB;t@A2&Vd;: (


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8erbah interval dosis


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8erbah dosis A2, 2,


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Ca?ss

Pada Steady State

amo"nt administered 1 amo"nt eliminated betFeen doses

M"lti'le dosin(

time

C'/ase 'ada k"r?a ini ditent"kan

oleh rate of elimination


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5oadin( dose4s6

time

C'

5oadin( dose 1 Cma3 3 $ol"me of distrib"tion

etracycline tA. 1 < ho"rs

:77m( loadin( dose diik"ti oleh .:7m( setia' < ho"rs


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Ca?ss 1 / ! Dose

Clearance!

Cavss

Men"r"nkan dosis dan men"r"nkan inter?al

Ca?ss teta', teta'i fl"kt"asi C' berk"ran(

1 dosin( inter?al


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%. t1/2dapat digunakan untuk memprediksi berapa waktu

yang diperlukan bila konsentrasi obat turun pada waktu

tertentu . Pada over dosis dan pengaturan dosis

t t1/2 . ln("1/"2) / &.



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6C #ml Obat dalam tbh


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Time

Concentration

A#C 2 ihitung menurutTrapeoidal &ule

6C #ml Obat dalam tbh

,nset of action

3

733 #!$

7

C!Dt 1 C

Area under the curve A#CArea under the curve

A#C


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Areaunder the curve A#CAreaunder the curve A#C

C 1 C7! e- k!t

monoe3'onential decay

C is an inte(ral

C 1 Dose A 4$ ! kel6

C 1 Dose A C5C51 Dose A C 4i!?!6

C51 /! Dose A C

-he 'alue is 'er use+ul +or calculatin& the amount o+ ru&

hich reaches the sstemic circulation )the a%solute %ioa'aila%ilit (

a+ter aministration o+ i++erent ru& proucts.

-he 'alue is 'er use+ul +or calculatin& the amount o+ ru&

hich reaches the sstemic circulation )the a%solute %ioa'aila%ilit (

a+ter aministration o+ i++erent ru& proucts.

PHA&AC/#T%CA( A(T/&$AT%+/-


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;The same AP% dosage form routeidentical in strength or conc


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-tudy Compound&eference Compoun

Time

Concentration

CmaD

TmaD

A#C

Approved Drug Products With Therapeutic Equivalence Evaluations. *5rded. *335. !A6C/&

eb site. Available at: http:66===.fda.gov6cder6ob6docs6preface6ecpreface.htmETherapeutic/uivalence0&elated Terms. Accessed -eptember *F *335.

G

G

Absolute bioavailability ;!


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A#C A#C

T T

Linear kinetics(most drugs)

Non-linear

kinetics(e.g. phenytoin)

+a'id 4bol"s6 i!?! inHection and "niform mi3in(

f h d i i d h h h l


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of the amo"nt administered thro"(ho"t the ?ol"me

of total body Fater>

Dose 1 c'lasma ! $d

$d1DoseAc'lasma


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D#G%E#N D#S+#B#%N $%5M*

5:8;I(A5!9

I(:7D%S*$

7d

C

PLASMA VS. MYOCARDIAL DIGOXIN


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LEVELS

P*+#P=*+5 $SC5+ *//*CS


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in&lecompartment moel

C

dAbsorption Eliminationka ke


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Penentuan harga Vd


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Pemberian obat secara intravena

g

Vd = ose i.v !"#

Lo Conc

time

$%trapolated estimate o& "#


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Apparent volume of distribution (Vd)

$L+E $* #@ST:@B+T@$9 *$: S$E #:+GS

' +d ;(

Cl i!?! 1 DoseAC

%ral Dose>

C5 '!o 1 /! %ral DoseAC

/ 1 fraksi dose menca'ai Lcentral 'ool )plasma B arin&an lm $eseim%an&an cepat &n plasma(

0

,#T

C

B(,,

(%+/&


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%$

Blood !lo= 2 Q

CA C+

B(,

,

/(%%$AT/

&ate of /limination 2 QCA4 QC+ 2 Q;CA0C+

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