7/25/2019 Kuliah MKDU-3
1/121
Clinical PharmacokineticsQuantitative Aspects :
Time course of drug in the body.
Prof. H.Achmad Basori
epartemen !armakologi
!" #$A%&
7/25/2019 Kuliah MKDU-3
2/121
7/25/2019 Kuliah MKDU-3
3/121
7/25/2019 Kuliah MKDU-3
4/121
7/25/2019 Kuliah MKDU-3
5/121
7/25/2019 Kuliah MKDU-3
6/121
Pharmacokinetics in Clinical Practice, Greenblat &Shader
Pharmacokinetics made easy, Dinald J BirkettPharmacokinetics forn Non-Mathematical, DW!Bo"rne
7/25/2019 Kuliah MKDU-3
7/121
'% tract
(iver
Blood
")$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$on microsome
0Aktif
0Tidak aktif
7/25/2019 Kuliah MKDU-3
8/121
7/25/2019 Kuliah MKDU-3
9/121
7/25/2019 Kuliah MKDU-3
10/121
Plasma Level vs Time Plots
#!$
P!%, i!m
7/25/2019 Kuliah MKDU-3
11/121
Plasma Site Concen- of
tration Action
Eects
P PD
Pharmacokinetics (PK) and
pharmacodynamics (PD)
Dose
Sam'lin( site
7/25/2019 Kuliah MKDU-3
12/121
7/25/2019 Kuliah MKDU-3
13/121
7/25/2019 Kuliah MKDU-3
14/121
Th
iopentalco
ncentration
(as
percentof
initialdose)
100
0
0
min!tes
1 10 100 1000
"lood
"rainm!scle adipose
Biphasic #istri"!tion $f Thiopental
7/25/2019 Kuliah MKDU-3
15/121
7/25/2019 Kuliah MKDU-3
16/121
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
7/25/2019 Kuliah MKDU-3
17/121
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(
7/25/2019 Kuliah MKDU-3
18/121
7/25/2019 Kuliah MKDU-3
19/121
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
7/25/2019 Kuliah MKDU-3
20/121
)ero %rder/irst order
te of elimination de'ends
'lasma concentration
rate of elimination is constant
and inde'endent of 'lasma
concentration
7/25/2019 Kuliah MKDU-3
21/121
7/25/2019 Kuliah MKDU-3
22/121
&ate of
eliminat1n
&ate of
eliminat1n
Blood drug conc Blood drug conc
Linear kinetics(most drugs)
Non-linear
kinetics(e.g. phenytoin)
A d
7/25/2019 Kuliah MKDU-3
23/121
&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 ...
7/25/2019 Kuliah MKDU-3
24/121
7/25/2019 Kuliah MKDU-3
25/121
Time
(ogPlasmaConcentration
7 . 8 9 : ;
7
77
777
7777
/irst %rder *limination
7/25/2019 Kuliah MKDU-3
26/121
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
7/25/2019 Kuliah MKDU-3
27/121
%+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
7/25/2019 Kuliah MKDU-3
28/121
%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
7/25/2019 Kuliah MKDU-3
29/121
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
7/25/2019 Kuliah MKDU-3
30/121
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
7/25/2019 Kuliah MKDU-3
31/121
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
7/25/2019 Kuliah MKDU-3
32/121
7/25/2019 Kuliah MKDU-3
33/121
7/25/2019 Kuliah MKDU-3
34/121
7/25/2019 Kuliah MKDU-3
35/121
The time to reach steady state is 89 t76*1s
7/25/2019 Kuliah MKDU-3
36/121
Concentration due to a single dose
Concentration due to repeated
doses
The time to reach steady state is 89 t76* s
Css
7/25/2019 Kuliah MKDU-3
37/121
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
7/25/2019 Kuliah MKDU-3
38/121
7/25/2019 Kuliah MKDU-3
39/121
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
7/25/2019 Kuliah MKDU-3
40/121
7/25/2019 Kuliah MKDU-3
41/121
able ! Dose fractionation desi(ns of an identical daily dose!
Tam +H $ikolaou ;*377< A $ovel Approach to Pharmacodynamic Assessment of
Antimicrobial Agents: $e= %nsights to osing &egimen esign. P(o- Comput Biol
>;[email protected]?5http:66===.ploscompbiol.org6article6info:doi673.75>[email protected]?5
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1001043http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.10010437/25/2019 Kuliah MKDU-3
42/121
00 m 8 h inf!sion
1000 m 8 h inf!sion
1000 m "ol!s inection 10 menit
M#C
7/25/2019 Kuliah MKDU-3
43/121
%bngan antara dosing rate dan
7/25/2019 Kuliah MKDU-3
44/121
%bngan antara dosing rate dan
konsentrasi drg !ada steady state+ss9 amont o/ drg in the body
Css9 concentration in steady state
R9 dosing rate
#osin interval/
Pada stead% state/
dosin rate 5 rate of elimination
: 5 A ss &
A ss5C ss d: 5 #3 5 Css d & 5 Css d 026783t
C ss512>> t134 #3(d )
A ss512>> t134#3
7/25/2019 Kuliah MKDU-3
45/121
Continos re!eating administration in
intravenos in$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:
7/25/2019 Kuliah MKDU-3
46/121
-elama continuous ;infusion< atau continuous
intermittent dosing ;oral dosing
7/25/2019 Kuliah MKDU-3
47/121
7/25/2019 Kuliah MKDU-3
48/121
?. 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.
7/25/2019 Kuliah MKDU-3
49/121
7/25/2019 Kuliah MKDU-3
50/121
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
7/25/2019 Kuliah MKDU-3
51/121
-i l d
7/25/2019 Kuliah MKDU-3
52/121
Time
PlasmaConcentration
&epeated doses 4
aintenance dose
Therapeutic
level
-ingle dose 4
(oading dose
7/25/2019 Kuliah MKDU-3
53/121
ultiple short i.v. inusions dari -mikacinultiple short i.v. inusions dari -mikacin
7/25/2019 Kuliah MKDU-3
54/121
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:
7/25/2019 Kuliah MKDU-3
55/121
*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
7/25/2019 Kuliah MKDU-3
56/121
7/25/2019 Kuliah MKDU-3
57/121
C
C SS
Css@3BB;t@A2&Vd;: (
7/25/2019 Kuliah MKDU-3
58/121
8erbah interval dosis
7/25/2019 Kuliah MKDU-3
59/121
8erbah dosis A2, 2,
7/25/2019 Kuliah MKDU-3
60/121
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
7/25/2019 Kuliah MKDU-3
61/121
5oadin( dose4s6
time
C'
5oadin( dose 1 Cma3 3 $ol"me of distrib"tion
etracycline tA. 1 < ho"rs
:77m( loadin( dose diik"ti oleh .:7m( setia' < ho"rs
7/25/2019 Kuliah MKDU-3
62/121
Ca?ss 1 / ! Dose
Clearance!
Cavss
Men"r"nkan dosis dan men"r"nkan inter?al
Ca?ss teta', teta'i fl"kt"asi C' berk"ran(
1 dosin( inter?al
7/25/2019 Kuliah MKDU-3
63/121
%. t1/2dapat digunakan untuk memprediksi berapa waktu
yang diperlukan bila konsentrasi obat turun pada waktu
tertentu . Pada over dosis dan pengaturan dosis
t t1/2 . ln("1/"2) / &.
Plasma Level vs Time Plots
7/25/2019 Kuliah MKDU-3
64/121
Plasma Level vs Time Plots
7/25/2019 Kuliah MKDU-3
65/121
6C #ml Obat dalam tbh
7/25/2019 Kuliah MKDU-3
66/121
Time
Concentration
A#C 2 ihitung menurutTrapeoidal &ule
6C #ml Obat dalam tbh
,nset of action
3
733 #!$
7
C!Dt 1 C
Area under the curve A#CArea under the curve
A#C
7/25/2019 Kuliah MKDU-3
67/121
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%+/-
7/25/2019 Kuliah MKDU-3
68/121
;The same AP% dosage form routeidentical in strength or conc
7/25/2019 Kuliah MKDU-3
69/121
-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 ;!
7/25/2019 Kuliah MKDU-3
70/121
7/25/2019 Kuliah MKDU-3
71/121
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
7/25/2019 Kuliah MKDU-3
72/121
of the amo"nt administered thro"(ho"t the ?ol"me
of total body Fater>
Dose 1 c'lasma ! $d
$d1DoseAc'lasma
7/25/2019 Kuliah MKDU-3
73/121
7/25/2019 Kuliah MKDU-3
74/121
7/25/2019 Kuliah MKDU-3
75/121
D#G%E#N D#S+#B#%N $%5M*
5:8;I(A5!9
I(:7D%S*$
7d
C
PLASMA VS. MYOCARDIAL DIGOXIN
7/25/2019 Kuliah MKDU-3
76/121
LEVELS
P*+#P=*+5 $SC5+ *//*CS
7/25/2019 Kuliah MKDU-3
77/121
in&lecompartment moel
C
dAbsorption Eliminationka ke
7/25/2019 Kuliah MKDU-3
78/121
Penentuan harga Vd
7/25/2019 Kuliah MKDU-3
79/121
Pemberian obat secara intravena
g
Vd = ose i.v !"#
Lo Conc
time
$%trapolated estimate o& "#
7/25/2019 Kuliah MKDU-3
80/121
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 $eseim%an&an cepat &n plasma(
0
,#T
C
B(,,
(%+/&
7/25/2019 Kuliah MKDU-3
115/121
%$
Blood !lo= 2 Q
CA C+
B(,
,
/(%%$AT/
&ate of /limination 2 QCA4 QC+ 2 Q;CA0C+