species extrapolation with pbpk models kannan krishnan université de montréal, canada

Species extrapolation with PBPK models

Kannan KrishnanUniversité de Montréal, Canada

Outline

Introduction Rat-Human extrapolation

Single chemicals Mixtures QSARs

Rat-Fish extrapolation PBPK modeling QSARs

Conclusions

PBPK Models and Interspecies Extrapolation

Adipose tissue

Richly perfused tissues

Liver

Poorly perfusedtissues

Lungs

Inhaled Exhaled

STRUCTURE INPUT

PARAMETERS

SIMULATIONS

PBPKProgram

RAT HUMAN

RAT

HUMAN

T

C

T

C

or

Functional Representation

Amount

tdAInput Output

dt

Blood flow to tissue, volume, partition coefficient

Functional RepresentationMetabolic Clearance

CK

CV

m max

Vmax = maximum velocity of metabolismKm = Michaelis-Menten constantC = concentration of chemical

Metabolizing enzyme, its levels, tissue volume

ExtrapolationExtrapolation

INVARIANT:INVARIANT:Species Species SPECIFIC:SPECIFIC:

Vmaxc

Km

Tissue:air PC

Blood:air PC

Flows

Volumes

[P-450]

Interspecies extrapolation of PK of chemicalsInterspecies extrapolation of PK of chemicals

Species Species SPECIFIC:SPECIFIC:

Blood:air PC

Flows

Volumes

[P-450]

Mixture PBPK Models and Interspecies Extrapolation

STRUCTUREINPUT

PARAMETERS

SIMULATIONS

ComputerComputerProgramProgram

RAT HUMAN

RAT

HUMAN

T

C

T

C

or

Arterial blood

FatFat

LungsLungs

Poorly perfusedtissues

Poorly perfusedtissues

Richly perfusedtissues

Richly perfusedtissues

LiverLiver

metabolism

Venous blood

A B C D E A B C D E

QSARs for PBPK Parameters

Fragment constant approach Ppbpk = nf·Cf

Multilinear regression (SPSS®) 46 VOCs, Fragments: CH3, CH2, CH, C, C=C,

H, Cl, Br, F, B-ring, 2 E1 substrates Cross-validation, external validation

Structure Input@Chemical

Exposure Condition

Yellow Indicates User Input

QSAR/PBPK model – Ethyl benzene

QSAR/PBPK model:Dichloromethane

Conceptual Representation

Inspired chemicalExpired chemical

Ven

ous

Blo

od

Arterial B

lood

Rest of Body

Kidneys

Muscle

Liver

Gills

Effective respiratory volume (Qv) Cex Cin

Cardiac ouput (Qc) Ca Cv

Gills

Pulmonary ventilation (Qv) Cex Cin

Cardiac output (Qc) Cv Ca

Lungs

Ventilation limited exchange : Pb = Cv/ Cex

Blood flow limited exchange : Pb = Ca/ Cin

Partition Coefficients

Tissue:water PCs Determinants of bioconcentration factors May vary between species (rat vs fish), if the

composition of tissues change from one species to another

Tissue components: lipids, water, proteins Lipids (neutral, phospho) + water

Tissue composition based Computation of PCs

ptwtptnte: oe:t F 0.7 F F 0.3 F P P

Po:e = n-octanol:env partition coefficientPt:e = tissue:env partition coefficientFnt = volume fraction of neutral lipids in tissueFpt = volume fraction of phospholipids in tissueFwt = volume fraction of water in tissue

Interspecies differences in mechanistic determinants (PCs)

Tissue and species

Neutral lipid eqvt

Water eqvt

Muscle

Rat 0.0117 0.7471

Human 0.0378 0.7573

Catfish 0.0041 0.7960

FHM 0.0194 0.8116

Trout 0.0244 0.7746

Interspecies extrapolation of tissue:air partition coefficients (Humans)

Log fat:air mecaniste

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

-0.5 0.5 1.5 2.5 3.5 4.5

Log EXPTL

Log

PR

ED

Log liver:air mecaniste

y = 0.9721x

R2 = 0.8686

-0.5

0

0.5

1

1.5

2

2.5

3

-0.5 0 0.5 1 1.5 2 2.5 3

Log EXPTL

Log

PR

ED

Log muscle:air mecaniste

y = 0.8858x

R2 = 0.814

-0.5

0

0.5

1

1.5

2

2.5

-0.5 0 0.5 1 1.5 2 2.5

Log EXPTL

Lo

g P

RE

D

R2 = 0.969Y = 0.973X

R2 = 0.993Y = 0.992X

R2 = 0.933Y = 0.886X

Interspecies extrapolation of tissue:air partition coefficients (Fish)

Channel catfish

y = 1.4883x

R2 = 0.9977

1

10

100

1000

10000

100000

1 10 100 1000 10000

Exptl PC

Pre

d P

C

Fathead minnow

y = 2.5499x

R2 = 0.9992

1

10

100

1000

10000

100000

1 10 100 1000 10000

Exptl PC

Pre

d P

C

Rainbow trout

y = 1.343x

R2 = 0.9981

1

10

100

1000

10000

100000

1 10 100 1000 10000

Exptl PC

Pre

d P

C

Application (chloroethane)

Log Poa = 0.373 +0.433 +0.785 = 1.6Log Pwa = -0.031 -0.225 +0.471 = 0.215

*101.6 + *100.215 = 2.87 Rat Pla

Trout Pla

0.0425 0.7176

*101.6 + *100.215 = 2.29 0.0261 0.7649

C C

H

H

H

H

H

CL

Magnitude of Interspecies Differences in Tissue:Water PCs

)BF 0.7 (BF )BF 0.3 (BF P

)AF 0.7 (AF )AF 0.3 (AF P A/B P

ptwtptntw: o

ptwtptntw: ow: t

Po :w = n-octanol:water partition coefficientPt :a = tissue:water partition coefficientFnt = volume fraction of neutral lipids in tissueFpt = volume fraction of phospholipids in tissueFwt = volume fraction of water in tissueA & B = two differents species

Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,0

0,5

1,0

1,5

2,0

2,5

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

b:w

rat

io

trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka

Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,0

0,5

1,0

1,5

2,0

2,5

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

b:w

rat

io

trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka

Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,0

0,5

1,0

1,5

2,0

2,5

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

b:w

rat

io

trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka

Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,0

0,5

1,0

1,5

2,0

2,5

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

b:w

rat

io

trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka

Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,0

0,5

1,0

1,5

2,0

2,5

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

b:w

rat

io

trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka

Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,0

0,5

1,0

1,5

2,0

2,5

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

b:w

rat

io

trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka

Calculated magnitude of interspecies differences in liver:water (Pl:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,00,51,01,52,02,53,03,54,04,55,0

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

l:w

rat

io trout/catfishmedaka/catfishtrout/medaka

Calculated magnitude of interspecies differences in liver:water (Pl:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,00,51,01,52,02,53,03,54,04,55,0

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

l:w

rat

io trout/catfishmedaka/catfishtrout/medaka

Calculated magnitude of interspecies differences in liver:water (Pl:w) partition coefficient as a function of

n-octanol:water partition coefficient (Po:w)

0,00,51,01,52,02,53,03,54,04,55,0

0,001 0,01 0,1 1 10 100 1000 10000

Po:w

Inte

rsp

ecie

s P

l:w

rat

io trout/catfishmedaka/catfishtrout/medaka

Interspecies extrapolation of metabolism constants Vmax in one species Allometrically scale to another species Assume Km to be species invariant Worked well for CYP2E1 subtrates

Structure-Metabolic Constants Relationship Modeling

0.7520.947R2

-2.07-. 353C=C

-.845-.211CH

7.08E-2.795CH3

-.320.269CH2

-1.544-1.451C

0.890.10PRESS/SSY

.584.453H (on C=C)

.296.810BR

.569.612CL

.382.734AC

Log Km Log VmaxcStructural feature

Application (chloroethane)

C C

H

H

H

H

H

CL

Log Vmaxc = 0.795 + 0.269 + 0.612 = 1.676 vs 1.79

101.68 * BW0.7 Human (BW=70 kg) = 937 µmol/hr

Rat (BW=0.25 kg) = 18.1 µmol/hr

Log Km = 0.071- 0.32 + 0.569 = 0.26 vs 0.19 µM

Interspecies extrapolation of metabolism constants Turnover rate for one species CYP concentration + tissue volume Interspecies extrapolation of Vmax… Current approach:

Classification of substrates (molecular volume, log P)

Isozyme-specific substrates ( in vitro QSARs) Species extrapolation based on protein [C]

and tissue volume

Extrapolation

INVARIANT:Species SPECIFIC:

Vmaxc

Km

Blood:air PC

Flows

Volumes

Enzyme [C]

Interspecies extrapolation of PK of organic chemicals

Species SPECIFIC:

Fluid PCs

Flows

Volumes

Enzyme [C]

In h ale d c h e mic a lE xh ale d c h e mic a l

Ve

nous

Blo

od A

rterial Bloo

d

R e s t o f B od y

K id ne y s

Bra in

Liv e r

G ills

QSAR-PBPK Modeling

Parameters

Equations

Tissu adipeux

Foie

Tissu pauvrement perfusé

Tissu richement perfusé

Poumons ou branchies

Sang artériel

San

g ve

ineu

x

Ca, Qc Cv, Qc

Cex, Qv Cin, Qv

Km, Vmax Métabolisme

CvL QL

QS

QR

QF

CvS

CvR

CvF

Simulations

Physiology

Temps

Co

ncen

trati

on

Rat

QSPR-PBPK Modeling: Interspecies extrapolation of tissue concentrations

0

5

10

15

20

25

30

35

0 5 10 15 20 25

Time (hr)

Tis

su

e co

nc

entr

atio

n (

mg

/L) Catfish

FHM

Trout

Rat

Human

DOSE EFFECT

QSAR

QSARs – An alternative paradigm

Tissue doseor Blood

Conc.QSAR QSAR

PK PD

• Relative contribution of the TK and TD processes• Extrapolations based on TK determinants

Conclusions

Interspecies differences in metabolic clearance and volume of distribution can be examined using mechanism-based QSARs

PBPK modeling uniquely allows the integration of such QSARs to simulate interspecies differences in PK profiles

QSAR-PBPK models facilitate internal dose based risk assessment in multiple species(lethal and non-lethal effects)

Frågor ?