Body clear- 1 Body clearance OCT 2010 PL Toutain

Body clear- 1

Body clearanceBody clearance

OCT 2010

PL Toutain

Body clear- 2


Body clearance, plasma (blood) clearance, systemic clearance, total clearance ...

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A fundamental relationship in steady-state conditions


Drug rate in Drug rate out

Dosage regimen Clearance

Clinician Patient'seliminatory process

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A fundamental relationshipA fundamental relationship

Dose = Body clearance x therapeutic concentration

Bioavailability

A dose can be determined rationally using a PK/PD approach

!

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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)

!

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• 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 ?

Why clearance should be evaluated ?

• for a practical purpose : dose computation

• for a mechanistic purpose: interpretation

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• Should be evaluated for any new drug entity

• Should be interpreted in physiological terms


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How to measure body clearance ?How to measure body clearance ?

Clbody = Dose (IV) / AUC (plasma, blood)

An IV administration is required!

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• 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

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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

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Measure of body clearanceMeasure of body clearance

• Accuracy of the dose

900800700600500400300200100

0Physicians (8) Pharmacists (4)

MeanRangeSD

Target dose

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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

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Clearancecomputation from excretion rate

Slope = clearance

Exc

reti

on

rat

e (d

x/d

t)

Plasma concentration

Possible non-linearity

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Physiological interpretation of blood (plasma) clearance

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 half-life of 25 days short, long or very long ?

?

YES, very long !

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• Difficult to answer because clearance has the dimension of a flow

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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

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Plasma clearancePlasma clearance

Cl = = Q x E =

definition model computation method

dx/dt

C

Dose

AUC

°

Concept not to confuse

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What reference system for plasma (blood) clearance?What reference system for plasma (blood) clearance?

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Reference system: clearance vs. half-lifeReference system:

clearance vs. half-life

Blood (plasma) Clearance (L/min/kg)

Blood (plasma) Half-life (min)

WatchCardiac output

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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

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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

°

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Interpretation of body clearanceInterpretation of body clearance

• Interpretation of body clearance consists of calculating an extraction ratio

Ebody = Body clearance (blood)

Cardiac output

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• 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

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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


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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

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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

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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

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• 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 ?

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Clearances are additiveClearances are additive

Clbody = Clrenal + Clhepatic + Clother

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Organ blood flow(% of cardiac output)

Organ blood flow(% of cardiac output)

• Liver: 30%

• Kidney: 20%

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Extraction ratioExtraction ratio

• Critical values

• High > 0.7

• Low < 0.3

this is not "magic" cutoff

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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%

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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


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Comparison of 2 molecules in the same class

Application of clearance concept

Application of clearance concept

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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

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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

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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?

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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:

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Drug A vs. Drug B: fu or Clint ?Drug A vs. Drug B: fu or Clint ?

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Drug A vs Drug B: fu?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?Drug A vs. Drug B: Clint?

• Hepatic clearance

Clint = Vmax

Km + Cfree

metabolic capacity

drug affinity

Catalysis

Binding

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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

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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

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Application of the clearance conceptApplication of the clearance concept

Interspecies comparison

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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


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Interspecies dose extrapolation


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• 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

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Dose species1 = Dose species2 x Cl species1

Cl species2

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• What to do when the clearance

for man is unknown ?

allometric approach

Extrapolation of the dose from animal to man


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Allometric relationshipLog parameter

Log BWLog y = a + b Log BWy = coefficient xBWb


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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

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Acute toxicity of anticancer drugshuman versus mouse

Acute toxicity of anticancer drugshuman versus mouse

Dose Ratio AUC Ratio

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To predict that a drug can be successfully marketed as an

oral dosage form


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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?

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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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

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Fmax = 1 - Eh

LiverFmax = 1 - Eh

Dose

EhFraction eliminated by first pass effect

Goal: to know Eh


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• Clh = Qh x Eh

• Eh = Clh / Qh

• Fmax = 1 - Eh = 1 - [Clh / Qh]

Maximal oral bioavailability

Goal : to know Clh


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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

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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?


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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

°



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• If Clplasma Clblood it is necessary to evaluate the Clblood

• Necessary to know the ratio:blood

plasmaor B/P



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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

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Blood or plasma clearance ?Blood or plasma clearance ?

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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)

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Answer from in vitro study only



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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



Eh

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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?

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Evaluation of a dose


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Drug rate in Drug rate out

Dosage regimen Clearance

Clinician Animal'seliminatory process

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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

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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

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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

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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

Documents

Body clear- 1 Body clearance OCT 2010 PL Toutain