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Quantitative Aspects :
Time course of drug in the body.
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
Dose
Site
Concentration
PK
of
Effects
Action
PD
Sampling site
Thiopental concentration
(as percent of initial dose)
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
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)
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
Linear
Non-linear
Rate of
elim
=
Rate of
admin
Rate of
elim
=
Rate of
admin
Blood
drug
conc
Rate of admin
Rate of admin
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
10000
1000
100
10
1
4
Time
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
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
No. of t1/2
1
2
3
4
5
Concentration achieved
(% of steady conc.)
50
75
87.5
94
97
Css
Concentration due to repeated
doses
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
2X mg min-1
Cp
X mg min-1
time
MIC
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.
MD
Plasma Concentration
Single dose
Loading dose
Therapeutic
level
Repeated doses
Maintenance dose
Time
Css max
Css min
Css av
concentration in plasma
(mg/L)
50
300 mg, 8h
40
30
20
10
0
0 12 24 36 48 60 72 84 96
time since start of dosing (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
time
Loading dose(s)
Loading dose = Cmax x Volume of distribution
Cp
time
Cavss = F . Dose
Clearance. T
T = dosing interval
Cavss
0
I.V
Concentration
100
C.Dt = AUC
Trapezoidal Rule
0
Onset of action
Time
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)))
No RCT
BIOEQUIVALENCE
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
Concentration
Ka
MBC
MIC
AUC
Tmax
Frel
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
Vd=Dose/cplasma
Dose = cplasma . Vd
536 L
C0
1.4 g/L
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
Penentuan harga Vd
Pemberian obat secara intravena
Extrapolated estimate of C0
Log Conc
time
Vd (L)
140
210
1050
~5000
Perhitungan Vd
mg/L
10
4
Time (h)
dengan VDD
Small Vd
Low tissue binding
Large Vd
Drug tightly bound
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
: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
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
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
Vd = D/C
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 = 0.693 x Vd/CL
t1/2 = 0.693/Kel
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
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
(mass/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
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
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
: Oral Dose
B
LO
O
D
CA
LIVER
BLOOD
OUT
CV
IN
Blood Flow = Q
ELIMINATED
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
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