Download BODY CLEARANCE

Body clearance
PL Toutain
OCT 2010
Body clear- 1
Body clearance
Body clearance, plasma (blood) clearance,
systemic clearance, total clearance ...
Body clear- 2
A fundamental relationship in
steady-state conditions
Drug rate in
Drug rate out
Dosage regimen
Clearance
Clinician
Patient's
eliminatory process
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A fundamental relationship
Body clearance x therapeutic concentration
Dose =
Bioavailability
!
A dose can be determined rationally using
a PK/PD approach
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Why is clearance a
fundamental PK parameter ?
• Clearance is the only parameter
measuring the ability of a body (or an
organ) to eliminate a drug
!
Ability is not synonymous with rate
of elimination (i.e. dx / dt)
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Body clearance
• Total clearance is a proportionality
factor which relates the rate of drug
elimination to a drug (plasma,
blood) concentration
• Rate of drug elimination = Cl x C
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Why clearance should be
evaluated ?
• for a practical purpose : dose computation
• for a mechanistic purpose: interpretation
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Body clearance
• Should be evaluated for any new
drug entity
• Should be interpreted in
physiological terms
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How to measure body clearance ?
Clbody = Dose (IV) / AUC (plasma, blood)
!
An IV administration is required
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Measure of the body clearance
Where does the relation Cl = Dose come from ?
AUC
• By definition
dx/dt
ClTOT =
C
 dx = ClTOT x C x dt
• Amount eliminated from 0 to infinity :



 0 dx =  0 ClTOT C dt = ClTOT  0C dt

ClTOT =
0 dx

0 C dt
=
Dose
AUC
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Measure of the body clearance
• Administration by IV of a known dose
• Measure of plasma (blood) concentration
0
!
10
20
Units of AUC (mg x L-1) x h = mg x h.L-1
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Measure of body clearance
• Accuracy of the dose
900
800
700
600
500
400
300
200
100
0
Mean
Range
SD
Target dose
Physicians (8)
Pharmacists (4)
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Why is an IV PK study required ?
• To provide essential PK drug parameters
• Clbody
• Volume of distribution
• True half-life of elimination (substance)
• To properly investigate the extravascular route
• to measure absolute bioavailability
• to determine the rate of absorption
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Excretion rate (dx/dt)
Clearance
computation from excretion rate
Slope = clearance
Possible non-linearity
Plasma concentration
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Physiological interpretation of
blood (plasma) clearance
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• Is a Amiodarone plasma clearance
of 1.9 mL/kg/min high, low or very low ?
?
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• Is a Amiodarone plasma clearance
of 1.9 mL/kg/min high, low or very low ?
?
• Is a Amiodarone plasma half-life of 25
days short, long or very long ?
YES, very long !
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• Is a Amiodarone plasma
clearance of 1.9 mL/kg/min
high, low or very low ?
• Difficult to answer because
clearance has the dimension
of a flow
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Why is clearance a flow ?
• By definition :
• Cl =
dx / dt
C
=
MT-1
MV-1
= VT-1
flow
• How to give a physiological meaning to this
flow ?
• by modeling clearance in terms of
physiological blood flow
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Plasma clearance
Cl =
dx/dt
°
=QxE=
C
definition model
Dose
AUC
computation method
Concept not to confuse
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What reference system for
plasma (blood) clearance?
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Reference system:
clearance vs. half-life
Blood (plasma)
Clearance (L/min/kg)
Cardiac output
Blood (plasma)
Half-life (min)
Watch
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Physiological interpretation of
plasma (blood) clearance
Heart
Clearing organs
(liver, kidney,…)
o
Clbody = Q x E
o
E
Q = cardiac output = o180 BW-0.19
with BW= kg et Q= ml/kg/min
E = overall extraction ratio
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The body (blood) clearance
• Model to interpret blood clearance
°
Clbody = Qcardiac output x Ebody
flow
flow
no unit
• Operationally, clearance is the blood
(plasma) volume which is totally cleared
of the analyte during a time unit
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Interpretation of body clearance
• Interpretation of body clearance consists
of calculating an extraction ratio
Ebody =
Body clearance (blood)
Cardiac output
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Cardiac output
5.6L/min
• From literature
• From allometric relationship
°
Q (mL/kg/min) = 180 BW (kg)-0.19
• Example : a 70 kg BW man
°
Q = 180 x 70-0.19 = 180 x 0.44 = 80 mL/kg/min
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Interpretation of body clearance
plasma
clearance
(ml/kg/min)
Penicillin
Gentamicin
Oxytetracycline
3.5
3.1
4.0
20kg
Tylosin
22
Cardiac output
(ml/kg/min)
180 x poids (kg)-0.19
Overall extraction
ratio (%)
3.5
3.1
4.0
22
Rem. 1 : half-life
(min)
30
75
360
54
100 ml/kg/min
Rem. 2 : we assume Clblood = Clplasma i.e. Cblood=Cplasma
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Clairance vs temps de demi-vie
Amiodarone
Clairance: 1.9 ml/kg/min
Temps de demi-vie: 25 jours
Amikacine
Clairance: 1.3 ml/kg/min
Temps de demi-vie: 2.3 heures
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Body (total) clearances
• Except for drugs metabolized in blood or
lungs, body clearance cannot be higher
than cardiac output
D (L/min/kg) = 180 BW-0.19 with BW in kg
BW
(kg)
Clmax
0.2
244
(ml/kg/min)
3
10
50
70
100
500
146
116
86
80
75
55
Assumption Cblood = Cplasma
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Is the Amiodarone blood
clearance high or low ?
• body clearance
1.9 mL/kg/min
• cardiac output:
70 mL/kg/min
• extraction ratio:
2.7%
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Is the Amiodarone extraction
ratio high or low ?
• Is E = 2.7% low or high ?
 Need of critical value
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Clearances are additive
Clbody = Clrenal + Clhepatic + Clother
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Organ blood flow
(% of cardiac output)
• Liver:
30%
• Kidney:
20%
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Extraction ratio
• Critical values
• High > 0.7
• Low < 0.3
this is not "magic" cutoff
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Interpretation of an overall extraction ratio
• Drug with a
high overall E
• Drug with a
low overall E
30 %
30 %
E  30%
E  70%
20%
E  70%
Overall E = 35%
20%
E  30%
Overall E = 15% Body clear- 40
Interpretation of body clearance
2. Is the body clearance (mL/kg/min)
high, medium or low ?
BW (kg)
0.2
3
20
50
70
100
500
Cl high
(E=0.35)
85
51
41
30
28
26
19
Cl medium
(E= 0.15)
37
22
17.4
13
12
11.3
8.25
Cl low
(E= 0.05)
12.2 7.3
5.8
4.3
4.0
3.75
2.75
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Application of clearance
concept
Comparison of 2 molecules
in the same class
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Interpretation of plasma clearance
Comparison of 2 drugs (MW=500 & 600) in the same class
Drug A
Drug B
Plasma
clearance
(ml/kg/min)
0.23
0.60
Plasma cardiac
output
180 BW-0.19
80 mL/kg/min
(0.23/80)x100=
0.29%
(0.60/80)x100=
0.75%
Overall extraction
ratio (%)
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Interpretation of plasma clearance
Comparison of 2 drugs in the same class
Drug A
Drug B
• Plasma clearance
(mL/kg/min)
0.23
0.60
• Overall extraction
ratio (%)
0.29%
0.75%
Conclusion: very low for both drugs
3 times lower for Drug A than for Drug B
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Drug A vs Drug B
• Overall extraction ratio is three times lower
for Drug A than for Drug B
• Was it possible to predict such a difference ?
• Probably : by in vitro assay
• What is the origin of the difference?
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Drug A vs. Drug B
Assumption:
• As MW is high : Clbody = Clh
• Both drugs have a low extraction
ratio thus :
fu x Clint
°
Clh = Qh x
°
Qh + fu x Clint
= fu Clint
fu and Clint can be determined by in vitro assays
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Drug A vs. Drug B: fu or Clint ?
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Drug A vs Drug B: fu?
Drug binding to circulating protein
In vitro studies e.g. equilibrium dialysis
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Drug A vs. Drug B: Clint?
• Hepatic clearance
Catalysis
metabolic capacity
Clint =
Vmax
Km + Cfree
drug affinity
Binding
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Vmax or Km?
Energy level
Penetration
Binding
(Km)
Catalysis
(Vmax)
High/covalent
Low /reversible
Core properties
Surface porperties
Polarity,
hydrophobicity,
lipophilicity
Reactivity,
electronic property
Steric hindrance
topography
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Drug A vs Drug B
• Origin of the difference
• fu : drug binding plasma protein
• Km: drug affinity for metabolic enzyme
• Vmax : catalytic efficiency
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Application of the
clearance concept
Interspecies comparison
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Application of the clearance concept
Interspecies comparison
Plasma (blood)
clearance
(ml/kg/min)
Cardiac output
(ml/kg/min)
Extraction
ratio
107
430
0.25
25
100
0.25
19.5
78
0.25
(10g)
(20 kg)
(80 kg)
Conclusion : all three species had the same overall
capacity to eliminate the drug
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Application of the
clearance concept
Interspecies dose
extrapolation
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Interspecies dose extrapolation
• Goal : to obtain the same exposure (AUC) for the
2 species
Dose = AUC x Cl
AUCman = AUCrat =
Dose man =
Dose rat
=
Clrat
Clman x
Dose man
Clman
Dose rat
Clrat
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Interspecies dose extrapolation
Dose species1 =
Dose species2 x Cl species1
Cl species2
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Interspecies dose extrapolation
Extrapolation of the dose from animal to man
• What to do when the clearance
for man is unknown ?
allometric approach
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Interspecies dose extrapolation
Allometric relationship
Log parameter
Log y = a + b Log BW
y = coefficient xBWb
Log BW
Body clear- 63
Interspecies dose extrapolation
Which dose of ketoprofen in goat ?
: 3 mg/kg/24 h ; Cl = 0.17L/kg/h
: Cl = 0.74 L/kg/h
Dose goat =
Dose cattle (3mg/kg) x Cl goat (0.74L/kg/h)
Clearancecattle (0.17 L/kg/h)
Dosegoat = 13
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Acute toxicity of anticancer drugs
human versus mouse
Dose Ratio
AUC Ratio
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Application of the
clearance concept
To predict that a drug can be
successfully marketed as an
oral dosage form
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Application of the clearance concept
Why can a drug not be administered by oral
route?
• Not absorbable
• formulation, solution
• P-glycoprotein…
• First pass effect
• in the digestive tract
• in the gut lumen
• liver
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Can a drug be successfully
marketed as an oral dosage form?
• How to answer this question only
from IV data
 by measuring total and renal
clearance to evaluate the non renal
clearance
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Hepatic first pass effect
vena
cava
DT
Liver
Absorption
portal vein
Absolute
bioavailability
F = 1 - (f1 + f1f2)
F = 0.25
Fraction eliminated (f2)
by first pass effect
f2 = 0.5
Fraction not
absorbed (f1)
f1 = 0.5
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Hepatic first pass effect
Dose
Liver
Fmax = 1 - Eh
Eh
Fraction eliminated by first pass effect
Fmax = 1 - Eh
Goal: to know Eh
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Hepatic first pass effect
Maximal oral bioavailability
• Clh = Qh x Eh
• Eh = Clh / Qh
• Fmax = 1 - Eh = 1 - [Clh / Qh]
Goal : to know Clh
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Can we predict whether a drug is
administrable by oral route?
YES: by measuring the total and renal clearances
to evaluate the non renal clearance (hepatic)
• Cltot = Clh + Clr + Clother
• Cltot = Dose / AUC
• Clrenal =dX/dt (urine)=
AUC
total amount excreted in urine
AUC
• Clh = Cltot - Clr
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Can a drug be administered by
oral route?
How to predict hepatic and renal clearance to
evaluate Fmax
1. Experimental data :
•
20 kg
• dose : 15 mg/kg, AUCplasma = 500 g.min.ml-1
• fraction eliminated by urine : 0.5 mg/kg
°
2. Literature data : Qh = 30 mL/kg/min
Body clear- 73
Can a drug be administered by
oral route?
2. Computation
• Cltot = 15 mg/kg / 500 g.min.ml-1 = 30 ml/kg/min
• Clr = 0.5 mg/kg / 500 g.min.ml-1 = 1 ml/kg/min
• Clh = 30-1 = 29 ml/kg/min
3. Interpretation
°h
• Fmax = 1 - Clh/Q
• Fmax = 1 - 29/30 = 0
4. Conclusion
This drug cannot be administered by oral route
Body clear- 74
Can a drug be administered by
oral route?
• If Clplasma  Clblood it is necessary to
evaluate the Clblood
• Necessary to know the ratio:
blood
plasma
or B/P
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The blood to plasma
concentration
• Permits conversion of the more easily
measured plasma concentrations and
their derived parameters into a blood
concentration measurement
• Application: calculate Fmax, the
maximal oral bioavailability
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Blood or plasma clearance ?
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Blood or plasma clearance?
• Blood
• Cb > Cp
and
• redistribution (departitionning) occurs during transit
throughout the clearing organ (10 sec for liver, 2 sec for
kidney cortex, 30 sec for kidney medulla)
 interpretation in terms of blood flow (ex.: labetol)
• Plasma
• Cp = Cb (antipyrine/alcool)
• Cp > Cb (maximum bias of 40%)
• Cb > Cp (slow reequilibration between red blood cells and
plasma during organ transit
 interpretation in terms of plasma flow (ex.: PAH)
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Can a drug be administered by
oral route?
Answer from in vitro study only
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Can a drug be administered by
oral route?
Model for hepatic clearance (Clh)
fu x Clint
o
Clh = Qh x
o
Qh + fu x Clint
fu : free fraction
Clint : intrinsic clearance
Eh
Fmax = 1 - Eh
Body clear- 80
Can a drug be administered by oral route?
Why know the intrinsic clearance from an in
vitro study?
Clint
°
fu, Qh
Eh
°
Qh
Clh hepatic clearance to evaluate indirectly
Clrenal
Cltotal
Dosage regimen, etc.
Body clear- 81
Application of the
clearance concept
Evaluation of a dose
Body clear- 82
A fundamental relationship in
steady-state conditions
Drug rate in
Drug rate out
Dosage regimen
Clearance
Clinician
Animal's
eliminatory process
Body clear- 83
Plasma clearance and dose estimation
Under equilibrium conditions
• entry rate = exit rate
•
F x dose
= Cl x Css,therap
dosage interval
Body clear- 84
Pharmacokinetics and
dosage regimen
dose
loading
dose
Cl/F
Vss/F
dosing
interval
t1/2
troughs and
peaks
Vss/F & t1/2
Body clear- 86
Poor
exposure
Local (BBB…)
(drug targeting; ADR)
overall
Poor oral
bioavailability
systemic
factor
Half-life
Distribution
Plasma
Binding
AUC
Barrier
Absorption
clearance
Transporters
Cell junctions
Physicochemical
Clearance
Renal
Hepatic
Metabolic
IR
CYP450
Polymorphism
Biliary
Others
1A2;2C9;2C19;2D6;3A4
Amino-acid
Glucuronide
Inhibition
CAR
Induction
Sulfate
AHR
PXR
The body clearance: summary
• The only parameter expressing the body's
ability to eliminate a drug
• comparison between drugs
• interspecies comparison
• Can be interpreted in physiological terms
• looking for limiting factors
• cardiac output
• metabolism, binding
Body clear- 89
The body clearance: summary
• Allows us computation of a dose
if the therapeutic drug
concentration is known
• Needs to be evaluated in vivo
requiring an IV study
• Can be estimated from in vitro
Body clear- 90