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Body clear- 1
Body clearanceBody clearance
OCT 2010
PL Toutain
Body clear- 2
Body clearanceBody clearance
Body clearance, plasma (blood) clearance, systemic clearance, total clearance ...
Body clear- 3
A fundamental relationship in steady-state conditions
A fundamental relationship in steady-state conditions
Drug rate in Drug rate out
Dosage regimen Clearance
Clinician Patient'seliminatory process
Body clear- 4
A fundamental relationshipA fundamental relationship
Dose = Body clearance x therapeutic concentration
Bioavailability
A dose can be determined rationally using a PK/PD approach
!
Body clear- 5
Why is clearance a fundamental PK parameter ?
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)
!
Body clear- 6
Body clearanceBody 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
Body clear- 8
Why clearance should be evaluated ?
Why clearance should be evaluated ?
• for a practical purpose : dose computation
• for a mechanistic purpose: interpretation
Body clear- 9
• Should be evaluated for any new drug entity
• Should be interpreted in physiological terms
Body clearanceBody clearance
Body clear- 10
How to measure body clearance ?How to measure body clearance ?
Clbody = Dose (IV) / AUC (plasma, blood)
An IV administration is required!
Body clear- 11
• Amount eliminated from 0 to infinity :
dx = ClTOT C dt = ClTOT C dt0 0
DoseAUC
0
Measure of the body clearanceMeasure of the body clearance
Where does the relation Cl = come from ?DoseAUC
• By definition
ClTOT = dx = ClTOT x C x dtdx/dt
C
ClTOT = = dx
C dt0
0
Body clear- 12
Measure of the body clearanceMeasure of the body clearance
• Administration by IV of a known dose
• Measure of plasma (blood) concentration
Units of AUC (mg x L-1) x h = mg x h.L-1!0 10 20
Body clear- 13
Measure of body clearanceMeasure of body clearance
• Accuracy of the dose
900800700600500400300200100
0Physicians (8) Pharmacists (4)
MeanRangeSD
Target dose
Body clear- 14
Why is an IV PK study required ?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
Body clear- 18
Clearancecomputation from excretion rate
Slope = clearance
Exc
reti
on
rat
e (d
x/d
t)
Plasma concentration
Possible non-linearity
Body clear- 19
Physiological interpretation of blood (plasma) clearance
Physiological interpretation of blood (plasma) clearance
Body clear- 20
• Is a Amiodarone plasma clearance of 1.9 mL/kg/min high, low or very low ?
?
Body clear- 21
• 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 !
Body clear- 22
• 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
Body clear- 23
Why is clearance a flow ?Why is clearance a flow ?
• By definition :
• Cl = = = VT-1 flow
• How to give a physiological meaning to this flow ?
• by modeling clearance in terms of physiological blood flow
dx / dt
C
MT-1
MV-1
Body clear- 25
Plasma clearancePlasma clearance
Cl = = Q x E =
definition model computation method
dx/dt
C
Dose
AUC
°
Concept not to confuse
Body clear- 26
What reference system for plasma (blood) clearance?What reference system for plasma (blood) clearance?
Body clear- 27
Reference system: clearance vs. half-lifeReference system:
clearance vs. half-life
Blood (plasma) Clearance (L/min/kg)
Blood (plasma) Half-life (min)
WatchCardiac output
Body clear- 28
Heart
Clearing organs (liver, kidney,…)
Clbody = Q x E
Q = cardiac output = 180 BW-0.19
with BW= kg et Q= ml/kg/minE = overall extraction ratio
E
o
o
o
Physiological interpretation of plasma (blood) clearance
Physiological interpretation of plasma (blood) clearance
Body clear- 29
The body (blood) clearanceThe 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
°
Body clear- 30
Interpretation of body clearanceInterpretation of body clearance
• Interpretation of body clearance consists of calculating an extraction ratio
Ebody = Body clearance (blood)
Cardiac output
Body clear- 31
• 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°
°
Cardiac outputCardiac output 5.6L/min
Body clear- 32
plasmaclearance(ml/kg/min)
Cardiac output (ml/kg/min)
Overall extractionratio (%)
Rem. 1 : half-life (min)
Rem. 2 : we assume Clblood = Clplasma i.e. Cblood=Cplasma
Penicillin
3.5
180 x
3.5
30
Gentamicin
3.1
poids (kg)-0.19
3.1
75
Oxytetracycline
4.0
100 ml/kg/min
4.0
360
Tylosin
22
22
54
20kg
Interpretation of body clearanceInterpretation of body clearance
Body clear- 33
Clairance vs temps de demi-vieClairance vs temps de demi-vie
AmiodaroneClairance: 1.9 ml/kg/min
Temps de demi-vie: 25 jours
AmikacineClairance: 1.3 ml/kg/min
Temps de demi-vie: 2.3 heures
Body clear- 34
Body (total) clearancesBody (total) clearances• Except for drugs metabolized in blood or
lungs, body clearance cannot be higher than cardiac outputD (L/min/kg) = 180 BW-0.19 with BW in kg
BW(kg)
Clmax
(ml/kg/min)
0.2
244
3
146
10
116
50
86
70
80
100
75
500
55
Assumption Cblood = Cplasma
Body clear- 35
Is the Amiodarone blood clearance high or low ?
Is the Amiodarone blood clearance high or low ?
• cardiac output: 70 mL/kg/min
• extraction ratio: 2.7%
• body clearance 1.9 mL/kg/min
Body clear- 36
• Is E = 2.7% low or high ?
Need of critical value
Is the Amiodarone extraction ratio high or low ?
Is the Amiodarone extraction ratio high or low ?
Body clear- 37
Clearances are additiveClearances are additive
Clbody = Clrenal + Clhepatic + Clother
Body clear- 38
Organ blood flow(% of cardiac output)
Organ blood flow(% of cardiac output)
• Liver: 30%
• Kidney: 20%
Body clear- 39
Extraction ratioExtraction ratio
• Critical values
• High > 0.7
• Low < 0.3
this is not "magic" cutoff
Body clear- 40
Interpretation of an overall extraction ratioInterpretation of an overall extraction ratio
• Drug with a high overall E
• Drug with a low overall E
30 %
E 70%20%
E 70%Overall E = 35%
30 %
E 30%
20%
E 30%Overall E = 15%
Body clear- 45
2. Is the body clearance (mL/kg/min) high, medium or low ?
BW (kg)
Cl high (E=0.35)
Cl medium (E= 0.15)
Cl low(E= 0.05)
0.2
85
37
12.2
3
51
22
7.3
20
41
17.4
5.8
50
30
13
4.3
70
28
12
4.0
100
26
11.3
3.75
500
19
8.25
2.75
Interpretation of body clearanceInterpretation of body clearance
Body clear- 46
Comparison of 2 molecules in the same class
Application of clearance concept
Application of clearance concept
Body clear- 47
Comparison of 2 drugs (MW=500 & 600) in the same class
Plasmaclearance(ml/kg/min)
Plasma cardiacoutput
Overall extraction ratio (%)
Drug A
0.23
180 BW-0.19
(0.23/80)x100=0.29%
Drug B
0.60
80 mL/kg/min
(0.60/80)x100= 0.75%
Interpretation of plasma clearanceInterpretation of plasma clearance
Body clear- 48
Drug A Drug B• Plasma clearance
(mL/kg/min) 0.23 0.60
• Overall extractionratio (%) 0.29% 0.75%
Interpretation of plasma clearanceInterpretation of plasma clearance
Conclusion: very low for both drugs 3 times lower for Drug A than for Drug B
Comparison of 2 drugs in the same class
Body clear- 49
Drug A vs Drug BDrug 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?
Body clear- 50
Drug A vs. Drug BDrug A vs. Drug B
• As MW is high : Clbody = Clh
• Both drugs have a low extraction ratio thus :
Clh = Qh x = fu Clint
fu x Clint
Qh + fu x Clint
°°
fu and Clint can be determined by in vitro assays
Assumption:
Body clear- 51
Drug A vs. Drug B: fu or Clint ?Drug A vs. Drug B: fu or Clint ?
Body clear- 52
Drug A vs Drug B: fu?Drug A vs Drug B: fu?
Drug binding to circulating protein
In vitro studies e.g. equilibrium dialysis
Body clear- 53
Drug A vs. Drug B: Clint?Drug A vs. Drug B: Clint?
• Hepatic clearance
Clint = Vmax
Km + Cfree
metabolic capacity
drug affinity
Catalysis
Binding
Body clear- 54
Vmax or Km?Vmax or Km?
Penetration Catalysis (Vmax)
Binding(Km)
En
erg
y le
vel
Low /reversible
High/covalent
Surface porperties Core propertiesPolarity, hydrophobicity, lipophilicity
Reactivity, electronic property
Steric hindrancetopography
Body clear- 55
Drug A vs Drug BDrug A vs Drug B
• Origin of the difference
• fu : drug binding plasma protein
• Km: drug affinity for metabolic enzyme
• Vmax : catalytic efficiency
Body clear- 56
Application of the clearance conceptApplication of the clearance concept
Interspecies comparison
Body clear- 57
Plasma (blood) clearance
(ml/kg/min)
107
25
19.5
Cardiac output (ml/kg/min)
430
100
78
Extractionratio
0.25
0.25
0.25(80 kg)
(20 kg)
(10g)
Conclusion : all three species had the same overall capacity to eliminate the drug
Interspecies comparison
Application of the clearance conceptApplication of the clearance concept
Body clear- 58
Interspecies dose extrapolation
Application of the clearance conceptApplication of the clearance concept
Body clear- 59
• Goal : to obtain the same exposure (AUC) for the 2 species
Dose = AUC x Cl
AUCman = AUCrat = =
Dose man =
Dose rat
Clrat
Dose man
Clman
Clman x Dose rat
Clrat
Interspecies dose extrapolationInterspecies dose extrapolation
Body clear- 60
Interspecies dose extrapolationInterspecies dose extrapolation
Dose species1 = Dose species2 x Cl species1
Cl species2
Body clear- 61
• What to do when the clearance
for man is unknown ?
allometric approach
Extrapolation of the dose from animal to man
Interspecies dose extrapolationInterspecies dose extrapolation
Body clear- 63
Allometric relationshipLog parameter
Log BWLog y = a + b Log BWy = coefficient xBWb
Interspecies dose extrapolationInterspecies dose extrapolation
Body clear- 64
Interspecies dose extrapolationInterspecies 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 mg/kg
Body clear- 65
Acute toxicity of anticancer drugshuman versus mouse
Acute toxicity of anticancer drugshuman versus mouse
Dose Ratio AUC Ratio
Body clear- 66
To predict that a drug can be successfully marketed as an
oral dosage form
Application of the clearance conceptApplication of the clearance concept
Body clear- 67
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
Application of the clearance conceptApplication of the clearance concept
Body clear- 68
Can a drug be successfully marketed as an oral dosage form?
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
Body clear- 69
vena cava
Liver DT
Absorption
portal vein
Absolute bioavailabilityF = 1 - (f1 + f1f2)F = 0.25
Fraction eliminated (f2)by first pass effectf2 = 0.5 Fraction not
absorbed (f1)f1 = 0.5
Hepatic first pass effectHepatic first pass effect
Body clear- 70
Fmax = 1 - Eh
LiverFmax = 1 - Eh
Dose
EhFraction eliminated by first pass effect
Goal: to know Eh
Hepatic first pass effectHepatic first pass effect
Body clear- 71
• Clh = Qh x Eh
• Eh = Clh / Qh
• Fmax = 1 - Eh = 1 - [Clh / Qh]
Maximal oral bioavailability
Goal : to know Clh
Hepatic first pass effectHepatic first pass effect
Body clear- 72
YES: by measuring the total and renal clearances to evaluate the non renal clearance (hepatic)
• Cltot = Clh + Clr + Clother
• Cltot = Dose / AUC
• Clrenal = =
• Clh = Cltot - Clr
Can we predict whether a drug is administrable by oral route?
Can we predict whether a drug is administrable by oral route?
dX/dt (urine)AUC
total amount excreted in urineAUC
Body clear- 73
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°
Can a drug be administered by oral route?
Can a drug be administered by oral route?
Body clear- 74
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• Fmax = 1 - Clh/Qh • Fmax = 1 - 29/30 = 0
4. Conclusion This drug cannot be administered by oral route
°
Can a drug be administered by oral route?
Can a drug be administered by oral route?
Body clear- 75
• If Clplasma Clblood it is necessary to evaluate the Clblood
• Necessary to know the ratio:blood
plasmaor B/P
Can a drug be administered by oral route?
Can a drug be administered by oral route?
Body clear- 76
The blood to plasma concentration
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
Body clear- 77
Blood or plasma clearance ?Blood or plasma clearance ?
Body clear- 78
Blood or plasma clearance?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)
Body clear- 79
Answer from in vitro study only
Can a drug be administered by oral route?
Can a drug be administered by oral route?
Body clear- 80
Clh = Qh x fu x Clint
Qh + fu x Clint
o
o
Model for hepatic clearance (Clh)
fu : free fractionClint : intrinsic clearance
Fmax = 1 - Eh
Can a drug be administered by oral route?
Can a drug be administered by oral route?
Eh
Body clear- 81
Clint
fu, Qh
Eh
Qh
Clh hepatic clearance to evaluate indirectly
Clrenal
Cltotal Dosage regimen, etc.
°
°
Why know the intrinsic clearance from an in vitro study?
Can a drug be administered by oral route?Can a drug be administered by oral route?
Body clear- 82
Evaluation of a dose
Application of the clearance conceptApplication of the clearance concept
Body clear- 83
A fundamental relationship in steady-state conditions
A fundamental relationship in steady-state conditions
Drug rate in Drug rate out
Dosage regimen Clearance
Clinician Animal'seliminatory process
Body clear- 84
Under equilibrium conditions
• entry rate = exit rate
• = Cl x Css,therap
F x dose
dosage interval
Plasma clearance and dose estimationPlasma clearance and dose estimation
Body clear- 86
dose loading dosing troughs and dose interval peaks
Cl/F Vss/F t1/2 Vss/F & t1/2
Pharmacokinetics and dosage regimen
Pharmacokinetics and dosage regimen
Local (BBB…)(drug targeting; ADR)overall
PlasmaBinding Barrier
systemicfactor
Poor oral bioavailability
Poorexposure
Absorption
Distribution clearance
AUCHalf-life
TransportersCell junctions
Physicochemical
Clearance
HepaticRenal
Metabolic Biliary
CYP450 Others
Polymorphism 1A2;2C9;2C19;2D6;3A4
IR
InductionInhibition
CAR
AHRPXR
Sulfate
GlucuronideAmino-acid
Body clear- 89
The body clearance: summaryThe 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- 90
The body clearance: summaryThe 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