1

Allometric scaling to predict

pharmacokinetic and pharmacodynamic
parameters in man
PL Toutain
UMR 181 Physiopathologie et Toxicologie Exprimentales
INRA, ENVT
ECOLE
NATIONALE
VETERINAIRE
T O U L O U S E
2
Introduction to allometry

Allometry (a term coined by Huxley
& Tessier 1936) is the study of
size and its consequences

3
Range of body size in mammals
Blue whale: >10
8
g
Shrew 2 g
Allometry is the study of size and its
consequences
Interspecies allometric scaling is based on the
assumption that there are anatomical, physiological
and biochemical similarities among animals which
can be described by simple mathematical models
4
Range of body size in mammals:
extrapolation within species
Adult to adult
Young to adult
5
Many allometric relationships have been
established between body size and organ weight
as well as body size and physiological process
6
y = 10x
0.6
R
2
= 1
0
20
40
60
80
100
120
140
160
180
0 20 40 60 80 100 120
Body weight
p
l
a
s
m
a

c
l
e
a
r
a
n
c
e
Simple allometry
Y=aBW
b
7
The power function
Y = aBW
b

Where Y is the parameter of interest, BW is the body weight, a & b are
the coefficient and exponent of the allometric equation respectively

The log transformation of this equation is represented as :

log Y = log a + b x logBW

Linear plot: slope=b and intercept=log A

the slope of the line (b) indicates the type of scaling relationship
8
Simple allometry:
the log-log transformation
y = 10x
0.6
R
2
= 1
1
10
100
1000
0.01 0.1 1 10 100
Body weight
p
l
a
s
m
a

c
l
e
a
r
a
n
c
e
logY=log a +b log BW

b=slope
Y=aBW
b
log a is the Y-intercept
9
0
2
4
6
8
10
12
0 2 4 6 8 10 12
Body weight

p
a
r
a
m
e
t
e
r

o
f

i
n
t
e
r
e
s
t
The scaling exponent (b) i.e. the slope
defines the type of scaling relationship
b=1.25
Y increase faster than BW
Positive allometry
b=0.75
Y increase slower than BW
Negative allometry
b=1.0
Y increase proportionally
with BW (isometry)
10
The assumption behind the log-log
transformation
It is assumed that there is a constant %CV
about the value of PK parameter
associated with BW being considered
11
The log-log transformation
log-log transformation of the data will visually minimize
the deviations from a regression line
A high R
2
(e.g. 0.95) do not guarantee that all the data
point will be close to the regression line
The extrapolation of this regression line to obtain a
predicted human value may have a great uncertainty
The regression process does not treat the weight of
each animal species comparably
Direct fitting of power function with incorporation of a
weighting strategy has been shown not to improve the
prediction performance
12
The log-log transformation
When there is a limited number of species
associated with the regression analysis,
each data point has the greatest impact on
the prediction of Y for animals whose
value of BW are closer to the deviant
observation
13
How does a the distribution of body weight used
in the regression analysis influence the
prediction of Y
For any species included in the regression
analysis, how does its location on the X-axis (i.e;
its value of BW relative to other observed data
points) influence prediction of Y
Can we anticipate the impact on prediction error
by the goodness of fit (R
2
) of the regression line
14
Number of species and the
regression line
When there is a limited number of species associated
with the regression analysis, each data point has the
greatest impact on the prediction of Y for animals whose
value of BW are closest to the deviant observation

When a midpoint species (dog in vet medecine) is the
source of the error, the change is primarily in the
intercept rather the slope; consequently the resulting
magnitude of prediction error is comparable throughout
the range of BW values examined
15
Influence on the predicted value in man of a 30% decrease
of the clearance value for a given species
species BW (kg) CL CL CL CL
Mouse 0.03 0.72 8 0.72 8 0.72 8 0.5046
Rat 0.2 2.99 2.09 2.99 2.99
Rabbit 4 28.28 28.28 28.28 28.28
monkey 8 47.56 47.56 47.56 47.56
dog 15 76.21 76.21 54.25 76.21
Man 70 242 247 200 212
predicted bias 0% +2% +17% +12%
16
ACCURACY OF ALLOMETRICALLY PREDICTED PHARMACOKINETIC
PARAMETERS IN HUMANS: ROLE OF SPECIES SELECTION

Huadong Tang and Michael Mayersohn
Drug Metabolism Disposition, 2005, 33 (9) 1288-1293
17
As demonstrated by both theoretical and literature experimentation,
rats had no significance in predicting human PK parameters as long as
the body weight of the rat is not the smallest in the species used in the
allometric relationship.
ACCURACY OF ALLOMETRICALLY PREDICTED PHARMACOKINETIC
PARAMETERS IN HUMANS: ROLE OF SPECIES SELECTION

Huadong Tang and Michael Mayersohn
Drug Metabolism Disposition, 2005, 33 (9) 1288-1293
18
Historical developments:
the direct extrapolation of doses
from animals to man
19
The Use of Body Surface Area as a Criterion of Drug
Dosage in Cancer Chemotherapy
Donald Pinkel
(Department of Pediatrics, Ronwell Park Memorial Institute
and
University of Buffalo School of Medicine, Buffalo, N.Y.)

Cancer Res 1958 28 853-856

20
Methotrexate
y = 0.3356x
0.642
R
2
= 0.9989
0
1
2
3
4
5
6
0 10 20 30 40 50 60 70 80
Body weight
d
o
s
e

p
e
r

d
a
y

i
n

m
g
Methotrexate
y = 0.3356x
0.642
R
2
= 0.9989
0.01
0.1
1
10
0.01 0.1 1 10 100
Body weight
d
o
s
e

p
e
r

d
a
y

i
n

m
g
Methotrexate y = 2.7102x + 0.0987
R
2
= 0.9947
0
1
2
3
4
5
6
0 0.5 1 1.5 2
surface area
d
o
s
e

p
e
r

d
a
y

i
n

m
g
Mouse=0.018
Rat=0.25
Infant=8
Adult=70
Child=20
Body weight in Kg
The use of body surface area as a criterion of
dosage regimen in cancer chemotherapy
(From D Pinkel :Cancer Res 1958 28 853-856)
21
Body surface area in man
The DuBois and DuBois formula
BSA (m) = 0.20247 x Height(m)
0.725
x Weight(kg)
0.425
The Haycock formula
BSA (m) = 0.024265 x Height(cm)
0.3964
x Weight(kg)
0.5378
The Gehan and George formula
BSA (m) = 0.0235 x Height(cm)
0.42246
x Weight(kg)
0.51456
The Boyd formula
BSA (m2) = 0.0003207 x Height(cm)
0.3
x Weight(grams)(0.7285 - (
0.0188 x LOG(grams) )
22
Comparison of toxicity data acquired during clinical studies of
18 anticancer agents with those obtained in mice, rats, dogs,
and rhesus monkeys uncovered close interspecies
correlations when doses were related to body surface, much
closer than when doses were related to mass. This finding
has guided numerous trials of anticancer and other agents.
23
Comparison of toxicity data on anticancer agents for
the Swiss mouse and man (on a mg per m
2
basis)
From Freireich et al 1966
Mouse LD
10
mg per m
2
M
a
x
i
m
u
m

t
o
l
e
r
a
t
e
d

d
o
s
e

(
m
g

p
e
r

m
2
)

1000
100
10
1.0
0.1
10
1000
Antimetabolites
Alkylating agents
Others
24
Observed and predicted dosage (mg per m
2
) in
man using animal system (Freireich & al 1966)
25
Interspecies scaling of maximum
tolerated dose of anticancer drugs
In general, small animal require larger dose than
human to reach the MTD.
Wanatabe et al used the LD10 mice data from
25 anticancer drugs and concluded that the
MTD in human can be predicted from mice LD1
using a scaling power of 0.75
Actually the use of a fixed exponent cannot be
justified
26
Data from Freireich & al 1966

Slope actually from 0.60 to 0.84
27
Body weight or body surface area?
BSA is not directly measured but
estimated with allometric equations
For a given species, it may exist several
equations predicting BSA
There is no advantage using BSA over
BW
28
29
What is exactly a Dose?
30
ED
50
=



ED
50
- is a hybrid parameter (PK and PD)
- is not a genuine PD drug parameter
Clearance x target EC
50

Bioavailability
PD
PK
The determination of an ED
50
or any ED
%

31
What is a dose?
ility Bioavailab
EC clearance
Dose
cal therapeuti plasma

=
ER Output Cardiac clearance
plasma
= _
75 0
321
.
) ( ) / ( _ kg BW day L output Cardiac =
32
Cardiac output in mammals
75 0
223
.
_ BW output Cardiac =
In mL per minute
Body Weight in kg
33
Interpretation of body clearance
Interpretation of body clearance
consists of calculating an extraction
ratio
E
body
=
Body clearance (blood)
Cardiac output
34
What is a dose?
ility Bioavailab
EC ER BW
Dose
cal therapeuti

=
75 0
321
.
g/L
g per day
Cardiac output (L per day)
35
Dose (IV) for an hepatic cleared drug with a low or
a high hepatic extraction ratio (ER)
cal therapeuti
EC
Km
V
fu Dose =
max
The plasma protein binding and metabolism activity are the major
determinants for the elimination of low hepatic clearance drugs;
therefore it is not expected to have a good allometric relationship
with BW across species for this kind of drug
cal therapeuti
EC BW Dose =
76 0
68
.
Low ER
High ER
Because hepatic blood flow is shown to have an allometric
relationship with BW, it is expected that the elimination of high
hepatic clearance drug can show an allometric relationship with BW
36
ED
50
=



Clearance x target EC
50

Bioavailability
PD
Interspecies scaling of
pharmacodynamic parameters
37
Interspecies scaling of
pharmacodynamic parameters
Very little information is available for the
prediction of pharmacodynamic (PD)
parameters from animal to man
It is conceptually difficult to accept that the
efficacy and potency of a drug will relate
with body weight of the species
38
Allometry of pharmacokinetics and
pharmacodynamics of the muscle relaxant
metocurine in mammals
39
Interspecies scaling of
pharmacodynamic parameters:
The case of Ketoprofen (sKTP)
Cat, goat, sheep, calf, horse
Endpoints: inhibition of the synthesis of
thromboxan (TXB2) and prostaglandinE2
(PGE2)
No relationship between IC
50
(or other PD
parameters) with BW
40
Modeling and allometric scaling of s(+)-ketoprofen
pharmacokinetics and pharmacodynamics: a
retrospective analysis
E.-I. LEPIST & W.J. JUSKO, J. Vet. Pharmacol. Therap. 27, 211-218, 2004
ANTIINFLAMMATORY DRUG
41
42
Interspecies scaling of pharmacodynamic
parameters:
the case of anaesthetic potency minimum
alveolar concentration (MAC)
Poor correlation between BW and MAC
for several inhalation anesthetics
Travis & Bowers 1991in: Toxicol Ind Health 1991 7 249-260

43
In vitro data: Drug affinity & drug potency
Drug potency
from in vitro:
MIC for
antibiotics
Benzodiazepine dose and benzodiazepine affinity
44
ED
50
=



Clearance x target EC
50

Bioavailability
Interspecies scaling of
pharmacokinetic parameters
45
Half-life
Systemic
exposure
Clearance
Volume of
distribution
bioavailability
Dosing regimen
How often?
Dosage regimen
How much
Absorption
46
Acute toxicity of anticancer drugs
human versus mouse
0
2
4
6
8
10
12
14
0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4
0
2
4
6
8
10
12
14
0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4
Dose Ratio
External dose
AUC Ratio
Internal dose
F
r
e
q
u
e
n
c
y

47
Interspecies scaling of clearance
48
Simple allometry: Diazepam
49
Scaling of antipyrine intrinsic clearance in 15
mammalian species
antipyrine in mammals
y = 8.2911x
0.8922
R
2
= 0.9713
0.1
1
10
100
1000
10000
0.01 0.1 1 10 100 1000
Body weight in kg
I
n
t
r
i
n
s
i
c

c
l
e
a
r
a
n
c
e

i
n

m
L

p
e
r

m
i
n
Boxenbaum & Fertig Europ J Drug Metab Pharmacokinet 1984 9 177-183
50
The concept of neoteny
Retention of juvenile
characteristics in the
adults of species
The modern man
retained its juvenile
characteristics of its
ancestors (apes)
through the
retardation of somatic
development for
selected organs
51
Exemple of Neoteny
52
Interspecies scaling of clearance
1. Simple allometry
2. Allometry with various biological
correction factors
1. Product of maximum life-span (MLP) and
clearance
2. Product of brain weight and clearance
3. Ratio of clearance and GFR
4. Two-term power equation
5. Incorporation of molecular structure parameters
6. incorporation of in-vitro data in in-vivo clearance
7. Correction for protein binding

53
Simple allometry & allometry with standard
correction factors (MLP and Brain weight)
Clearance or Clearance multiplied by MLP or Brain
weight of several species are plotted against BW on
a log-log plot
b
aBW Clearance=
b
aBW MLP Clearance =
b
aBW t BrainWeigh Clearance =
54
Product of maximum life-span (MLP) and
clearance
The clearance of different species are multiplied by
their respective MLP and are plotted against a
function of BW on a log-log scale
5
10 18 8

=
.
) (
b
man
Clearance MLP a
Clearance
225 0 636 0
4 185
. .
* _ * . ) (

= BW weight Brain years MLP
55
Prediction of Cefazolin Clearance in man:
standard vs. corrected allometry (MLP)
Cefazolin y = 5.3801x
0.7828
R
2
= 0.9982
0.1
1
10
100
1000
0.01 0.1 1 10 100
Body weight
C
l
e
a
r
a
n
c
e
cefazolin MLP
y = 3.7432x
1.1068
R
2
= 0.9906
0.01
0.1
1
10
100
1000
0.01 0.1 1 10 100
Body weight in kg
C
L

X


M
L
P
Simple allometry
Predicted: 141 mL/min
Actual: 61 mL/min
Error: 131%
Allometry with MLP as a correcting factor
Predicted: 50.55mL/min
Actual: 61mL/min
Error:17.1%
56
Selection of a standard correction factor
and the so-called rule of the exponent
The random use of the different correction factors is of
no practical value
Mahmood & Balian 1996 investigated 40 drugs and
found that the exponent of the simple allometry ranged
from 0.35 to 1.39
Based on these exponents ,it was found that there are
conditions under which only one of the three methods
can be used preferentially for reasonably accurate
prediction of clearance

Mahmood & Balian 1996 xenobiotica 26 887-895
57
The rule of exponents
to predict clearance in man
Mahmood & Balian 1996
1. 0.55 b <0.71 : no correction factor is
necessary

2. 0.71 b <1.00 MLP should be incorporated
into scaling method

3. B>1.00 Brain weight should be incorporated
into the scaling method
58
The rule of exponents
to predict clearance in man for 50 drugs
Methods % Mean absolute error
(MAE)
Simple allometry 106
CL x MLP 40
CL x brain Weight 49
Rule of exponents 25
Mahmood In interspecies pharmacokinetic scaling 2005 pp49
59
103 compounds investigated
Standard allometry and allometry including various correction factor
(MLP, brain weight, GFR) were performed
Scaling were performed on all compounds universally and on
segregated subset based on allometric exponent, clearance,
physicochemical properties etc
776 allometric combinations with 27913 outcomes were preformed
A predicted-to-observed clearance ratio of 0.5 to twofold was
preselected as the criterion for predictive success
A Comprehensive Analysis of the Role of Correction
Factors in the Allometric Predictivity of Clearance from
Rat, Dog, and Monkey to Humans

RAKESH NAGILLA, KEITH W. WARD
60
Nagilla & Ward JPS 2004
61
No correction MLP
Brain weight Rule of the exponents
Nagilla & Ward 2004
62
A Comprehensive Analysis of the Role of Correction
Factors in the Allometric Predictivity of Clearance from
Rat, Dog, and Monkey to Humans
When all three species were utilized in scaling
using simple allometry, 48 of 103 compounds
yielded a ratio (predicted/observed) that was not
within twofold of the observed value
Incorporation of the empirical correction factor
MLP or brain weight, either universally or
judiciously according to the rule of exponents,
failed to improve the predictive performance of
the method.
63
A Comprehensive Analysis of the Role of Correction
Factors in the Allometric Predictivity of Clearance from
Rat, Dog, and Monkey to Humans
The success rate of allometric scaling
ranged from 18 to 53%
None of the correction factor resulted in
substantially improved predictivity
None of the methods attempted in this
study achieved a success rate greater
than that observed by simply estimating
human clearance based on monkey
hepatic extraction
64 Nagilla & Ward 2004
%

o
u
t
l
i
e
r
s

Influence of species, routes of elimination and correction factors
0.5-to twofold window
66
Value of the allometric approach
Conclusion: the prospective allometric
scaling , with or without correction factors,
represent a suboptimal technique for
estimating human clearance based on in
vivo preclinical data
Nagilla & Ward J Pharmac Sci 2004 1 2522-
2534

67
See also Obach & al for the value of
allometry as a predictive tool
68
Correction factors for renally and biliary
excreted drugs
Renally excreted drugs



Biliary excreted drugs
b
aBW GFR Clearance = /
B
aBW flow Bile Cl = _
b
aBW UDPGT Cl =
UDPGT=UDP-glucuronyltransferase activity
69
Interspecies scaling of clearance
1. Simple allometry
2. Allometry with various biological correction factors
1. Product of maximum life-span (MLP) and clearance
2. Product of brain weight and clearance
3. Ratio of clearance and GFR
4. Two-term power equation
5. Incorporation of molecular structure
parameters
6. incorporation of in-vitro data in in-vivo clearance
7. Correction for protein binding

70
Incorporation of molecular structure
parameters
Wajima et al. 2002 suggested to use descriptors of
drugs related to clearance to predict clearance in man
e.g.:
Molecular Weight ,Calculated partition coefficient (c log P;
Number of hydrogen bound acceptors (Ha)).
Then using some types of regression (multiple linear
regression analysis, partial least square analysis or
artificial neuronal network), a regression equation can
be derived to predict clearance in man:

.... _ ) ( ) ( ) ( + + + + = bounding Hydrogen MW Cl Log CL Log CL Log
dog rat man
o ; | o
71
Interspecies scaling of clearance
1. Simple allometry
2. Allometry with various biological correction
factors
1. Product of maximum life-span (MLP) and clearance
2. Product of brain weight and clearance
3. Ratio of clearance and GFR
4. Two-term power equation
5. Incorporation of molecular structure
parameters
6. Correction for protein binding
7. incorporation of in-vitro data in in-vivo
clearance

72
Correction for protein binding
Protein binding varies considerably among
animal species which in turn can influence the
distribution and elimination of drugs
Theoretically unbound clearance should be
predicted with more accuracy than the total
clearance but in practical terms this is not the
case (Mahmood, 2005)
Actually, the correction for binding simply adds
more variability to the unbound clearance of the
species

73
Interspecies scaling of clearance
1. Simple allometry
2. Allometry with various biological correction factors
1. Product of maximum life-span (MLP) and clearance
2. Product of brain weight and clearance
3. Ratio of clearance and GFR
4. Two-term power equation
5. Incorporation of molecular structure parameters
6. Correction for protein binding
7. incorporation of in-vitro data in in-
vivo clearance
74
Dose for an hepatic cleared drug with a low
hepatic ER and a total absorption
cal therapeuti
EC
Km
V
fu Dose =
max
The plasma protein binding and metabolism activity are the major
determinants for the elimination of low hepatic clearance drugs;
therefore it is not expected to have a good allometric relationship with
BW across species for this kind of drug as it is the case for antipyrine
( the Clint of antipyrine in man is only one-seventh of that which would
be predicted from other species)
75
Incorporation of in vitro data in in vivo
clearance (Lav et al. 1997)
Clearances are normalized with in vitro data
providing a more rational (mechanistic) approach for
predicting metabolic clearance in man
b
s hepatocyte animal
s hepatocyte human
animal
BW a
Cl
CL
Cl =
) (
) (
For 10 extensively metabolized compounds, adjusting the in vivo
clearance in the different animal species for the relative rates of
metabolism in vitro dramatically improved the prediction of human
clearance compared to the approach in which clearance is directly
extrapolated using BW
Lave et a., J Pham Sci., 1997, 86: 584-590
77
b
BW a Cl =
s hepatocyte animal
s hepatocyte human
vivo in animal
Cl
Cl
Cl
_
_
_

R
2
=0.525
Predicted human clearance=196ml/min
R
2
=0.976
Predicted human clearance=100mL/min

Interspecies Scaling of Bosentan, A New Endothelin
Receptor Antagonist and Integration of in vitro Data into
Allometric Scaling
Thierry Lave, Philippe Coassolo, Genevive Ubeaud, Roger Brandt, Christophe Schmitt, Sylvie Dupin,
Daniel Jaeck ane Ruby C. Chou - Pharmaceutical Research, 13(1), 1996
78
Hepatocytes vs microsomes
Absence of phase II metabolism on liver
microsomes, which could result in enzyme
inhibition due to the accumulation of the
oxidative metabolites
81
Incorporation of in-vitro data in in-
vivo clearance
Methods %MAE
Simple allometry 164
CL x Brain Weight 61
In-vitro method 40
Rule of exponent 38
Data of Lave al (J Pham Sci 1997 86 584-590) on 10 extensively
metabolised drugs reanalysd by Mahmood 2005
82
Extrapolation of bioavailability
83
ED
50
=




Clearance x target EC
50

Bioavailability
Bioavailability in man:
prediction from rodents, primates & dogs ED
%
84
Absorption & Bioavailability (F)
where
f
abs
= fraction absorbed from GI lumen
f
g
= fraction metabolized by GI tissue
ER
H
= hepatic extraction ratio, equivalent
to hepatic first pass effect
1 - F = presystemic elimination

) ( ) ( %
H g abs
ER f f F = 1 1
85
Bioavailability in man:
prediction from rodents, primates & dogs
From Grass ADDR 2002
pp433
87
Extrapolation of Vss
88
Interspecies scaling of volumes of
distribution (Vd)
Where Vp, is the volume of plasma; Vt is tissue
volume and f
up
and f
ut
are the fraction of
unbound drug in plasma and tissues
respectively
Usually a change in f
ut
has a greater effect than
f
up
on Vss
ut
up
t p
f
f
V V Vss + =
89
The minimal volume of distribution is
7.5 L (0.1 L/kg)
VD = 7.5 + 7.5 x fu + 27L x
fu
p

fu
T

Volume of
distribution of
albumin
Drug highly
bound to
plasma protein
fu=very smal
No partitioning
No tissue binding
V = 7.5 L (not 3 L) which is the VD of albumin

Note: plasma volume = 3 L but plasma protein (and
drug) diffuse out of vascular space and thus protein
(and drug) will return through the lymphatic system
90
Interspecies scaling of volumes of
distribution (Vd)
Because there is no allometric relationship
between protein binding and BW, it will be
difficult to project the Vd of drug in humans from
data in animals
When a drug has a low binding to plasma and
tissue proteins or when a drug only distribute
extracellularly, the Vd of the drug reflect total
body water or extracellular water
In these cases, the Vd in human can be predicted
from data in animals because both the total body
water and extracellular water decrease as animal size
increases in an allometric manner.
91
Volume of distribution of propranolol
Vfree (Unbound)
Vtotal
For propranonol, Vf should be similar in humans and other species
However this is not a general rule (e.g. large difference for Vf between
species for Beta-lactam antibiotics)
92
Interspecies scaling of volumes of
distribution (Vd)
Vc is the most important volume parameter
which can be predicted with much more
accuracy than Vss or V
The exponent of all three volume revolve around
1.0 indicating that there exist a direct
relationship between BW and volume
Correction for protein binding is not much help in
improving the prediction of vomume in man
93
Extrapolation of half-life
94
Interspecies scaling of elimination
half-life
Application of HL to the first time dosing to
man is limited
HL is an hybrid parameter (clearance and
Vd)
Conceptually, it is difficult to establish a
relationship between HL and BW
Unlike clearance and Vd , the correlation
of HL with BW has been found to be poor

95
R2=0.14
R2=0.90
R2=0.94
HL
CL
VD
Allometric analysis of
ciprofloxacin half-life,
clearance and volume
of distribution across
mammals
Poor correlation for HL
while correlation for
CL and Vss are good
96
97
Prediction of drug clearance in
children from adults
Origin of the difference between children
and adults
Variation in body composition
Difference in liver and kidney function
98
Age-related changes clearance
Morphine
Fentanyl
99
Prediction of drug clearance in
children from adults
41 drugs considered
124 observations in children of different
age groups
Infant, children, adolescent (from 1 day to
17 years)
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Tested models
0 1 80 0 75 0 . _ _ . _ _ .
_
or or
adult
child
adult child in
BW
BW
Cl CL

=
1. Classical allometric equation with different exponents
2. Correction of adult clearance by the estimated liver and
kidney weight in children
3. The clearance were estimated using a specific method for a
given age (decision tree)
Child<1year: exponent=1
Child >1 years but <5 years: correction by liver and kidney weight
Child >5 years : allometric exponent of 0.75, 0.80 or 0.85
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Results
1. No single method was suitable for all
drugs or for all age groups
2. The %RMSE i.e. (MSE)
0.5
was almost
similar for exponent 0.75, 0.80 and 0.85
as well as the approach based on the
liver and kidney weights
3. The lowest RMSE was seen with the
mixed approach

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Percent root mean square (RMSE) and percent error in the
prediction of clearance in children by several methods
Tested Exponents: 0.75, 0.89, 0.85 and 1.0
L+K: liver and kidney weights correction
Mixed : decision tree based upon age
Number of predictions in error
(>100%) for 124 predictions
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Children <1 year old
The exponent 0.75 overpredicted the
clearance by several folds
When exponent 1.0 (no exponent) was
used on the BW the prediction of
clearance was fairly reasonable and far
less erratic than 0.75
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Children from 1 to 5 years old
The best approach appears to be the liver
and kidney weights corrections
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Children >5 years old
One can use any exponent:
(0.75, 0.80 or 0.85)
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Allometry in veterinary medicine
107
108
109
Conclusions:
Advantages of interspecies PK scaling
Simple and easy to use
Require plasma concentration-time data from
which PK parameters are calculated
Knowledge of elimination pathways, and plasma
protein binding may be helpful but not necessary
Data analysis is short
80% success rate if incorporation of hepatocytes
information's
110
Limits of allometic scaling
111
112
Limits of allometric scaling
113
For more information, consult the
Mahmood book