ECOLE NATIONALE VETERINAIRE TOULOUSE

Allometric scaling to predict pharmacokinetic and pharmacodynamic parameters in man

PL Toutain
UMR 181 Physiopathologie et Toxicologie Exprimentales INRA, ENVT

Introduction to allometry

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

Range of body size in mammals

Shrew 2 g

Blue whale: >108 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

Range of body size in mammals: extrapolation within species

Adult to adult

Young to adult
4

Many allometric relationships have been established between body size and organ weight as well as body size and physiological process

Simple allometry
180 160 140 plasma clearance 120 100 80 60 40 20 0 0 20 40 60 Body w e ight 80 100 120
0.6 y = 10x R2 = 1

Y=aBWb

The power function

Y = aBWb
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
7

Simple allometry: the log-log transformation

1000 y = 10x0.6 R2 = 1

logY=log a +b log BW
plasma clearance 100

b=slope

10

Y=aBWb
1 0.01 0.1 1 Body weight 10 100

log a is the Y-intercept

The scaling exponent (b) i.e. the slope defines the type of scaling relationship
12

b=1.25
parameter of interest
10

Y increase faster than BW Positive allometry

b=1.0
Y increase proportionally with BW (isometry)

0 0 2 4 6 8 10 12

b=0.75

Body weight

Y increase slower than BW Negative allometry

9

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

10

The log-log transformation

log-log transformation of the data will visually minimize the deviations from a regression line A high R2 (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
11

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

12

 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 (R2) of the regression line
13

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

14

Influence on the predicted value in man of a 30% decrease of the clearance value for a given species
species Mouse BW (kg) 0.03 CL 0.72 8 CL 0.72 8 CL 0.72 8 CL 0.5046

Rat Rabbit monkey dog

0.2 4 8 15

2.99 28.28 47.56 76.21

2.09 28.28 47.56 76.21

2.99 28.28 47.56 54.25

2.99 28.28 47.56 76.21

Man predicted

70 bias

242 0%

247 +2%

200 +17%

212 +12%
15

ACCURACY OF ALLOMETRICALLY PREDICTED PHARMACOKINETIC PARAMETERS IN HUMANS: ROLE OF SPECIES SELECTION Huadong Tang and Michael Mayersohn

16

Drug Metabolism Disposition, 2005, 33 (9) 1288-1293

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

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.

17

Historical developments: the direct extrapolation of doses from animals to man

18

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

19

The use of body surface area as a criterion of dosage regimen in cancer chemotherapy
(From D Pinkel :Cancer Res 1958 28 853-856)
6

Methotrexate

y = 0.3356x0.642 R2 = 0.9989
6

Methotrexate
dose per day in mg
5 4 3 2 1 0 0 0.5 1

y = 2.7102x + 0.0987 R2 = 0.9947

dose per day in mg

5 4 3 2 1 0 0 10 20

Body weight

30

40

50

60

70

80

1.5

surface area

Mouse=0.018
dose per day in mg

Methotrexate
10

y = 0.3356x 2 R = 0.9989

0.642

Body weight in Kg

0.1

Infant=8 Rat=0.25

Child=20 Adult=70

0.01 0.01

0.1

10

100

Body weight

20

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) )
21

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.
22

Comparison of toxicity data on anticancer agents for the Swiss mouse and man (on a mg per m2 basis)
From Freireich et al 1966
1000

Maximum tolerated dose (mg per m2)

100

10

Antimetabolites Alkylating agents Others

1.0

0.1 10

Mouse LD10 mg per m2

1000 23

Observed and predicted dosage (mg per m2) in man using animal system (Freireich & al 1966)

24

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
25

Slope actually from 0.60 to 0.84

Data from Freireich & al 1966
26

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

27

28

What is exactly a Dose?

29

The determination of an ED50 or any ED% PD ED50 = Clearance x target EC50 Bioavailability PK ED50 - is a hybrid parameter (PK and PD) - is not a genuine PD drug parameter
30

What is a dose?
Cardiac _ output (L / day ) = 321 BW (kg )0.75

clearance plasma = Cardiac _ Output ER

clearance plasma ECtherapeutical Bioavailability

Dose =

31

Cardiac output in mammals

Cardiac _ output = 223 BW

In mL per minute

0.75

Body Weight in 32 kg

Interpretation of body clearance

Interpretation of body clearance consists of calculating an extraction ratio

Ebody =

Body clearance (blood) Cardiac output

33

What is a dose?
Cardiac output (L per day) g/L
Dose = 321 BW 0.75 ER ECtherapeutical Bioavailability

g per day
34

Dose (IV) for an hepatic cleared drug with a low or a high hepatic extraction ratio (ER)

Low ER

V max Dose = fu ECtherapeutical Km

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

High ER

Dose = 68BW 0.76 ECtherapeutical

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 35

Interspecies scaling of pharmacodynamic parameters

PD ED50 = Clearance x target EC50 Bioavailability

36

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

37

Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals

38

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 IC50 (or other PD parameters) with BW
39

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

40

41

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

42

In vitro data: Drug affinity & drug potency

Drug potency from in vitro: MIC for antibiotics

Benzodiazepine dose and benzodiazepine affinity

43

Interspecies scaling of pharmacokinetic parameters

ED50 =

Clearance x target EC50 Bioavailability

44

Volume of distribution

Absorption

Clearance
bioavailability

Half-life

Systemic exposure

Dosing regimen How often?

Dosage regimen How much 45

Acute toxicity of anticancer drugs human versus mouse

Dose Ratio External dose
14 12
14 12 10 8 6 4 2

AUC Ratio Internal dose

Frequency

10 8 6 4 2 0 0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4

0 0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4

46

Interspecies scaling of clearance

47

Simple allometry: Diazepam

48

Scaling of antipyrine intrinsic clearance in 15 mammalian species

antipyrine in mammals
10000 Intrinsic clearance in mL per min 1000 100 10 1 0.1 0.01 y = 8.2911x 0.8922 R2 = 0.9713

0.1

10

100

1000

Body weight in kg

Boxenbaum & Fertig Europ J Drug Metab Pharmacokinet 1984 9 177-183

49

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
50

Exemple of Neoteny

51

Interspecies scaling of clearance

1. Simple allometry

1. Allometry with various biological correction factors

1. Product of maximum life-span (MLP) and clearance 2. Product of brain weight and clearance Ratio of clearance and GFR Two-term power equation Incorporation of molecular structure parameters incorporation of in-vitro data in in-vivo clearance Correction for protein binding

1. 2. 3. 4. 5.

52

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

Clearance = aBW b
Clearance MLP = aBW
b
b

Clearance BrainWeight = aBW

53

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

Clearance man

a(MLP Clearance ) = 5 8.18 10

MLP ( years ) = 185.4 * Brain _ weight 0.636 * BW 0.225

54

Prediction of Cefazolin Clearance in man: standard vs. corrected allometry (MLP)

C e fa z o lin y = 5 .3 8 0 1 x
2 0.7828

R = 0 .9 9 8 2
10 00
1000 100 CL X MLP 10 1 0.1 0.01 0.01

cefaz olin MLP

y = 3.7432x 2 R = 0.9906

1.1068

100 Clearance

10

0 .1 0.01

0.1

1 B o d y w e ig h t

10

100

0.1

1 Bo dy w e ig h t in kg

10

100

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%
55

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

56

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
57

The rule of exponents to predict clearance in man for 50 drugs

Methods Simple allometry CL x MLP CL x brain Weight Rule of exponents % Mean absolute error (MAE) 106 40 49 25
58

Mahmood In interspecies pharmacokinetic scaling 2005 pp49

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

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

59

Nagilla & Ward JPS 2004

60

No correction

MLP

Brain weight

Rule of the exponents

61

Nagilla & Ward 2004

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.
62

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
63

Influence of species, routes of elimination and correction factors

% outliers
Nagilla & Ward 2004

0.5-to twofold window

64

Data set segregated based on physicochemical properties

Within the classification of polar surface area (PSA), number of hydrogen bounds acceptors, cLogP and number of rotable bounds, the predictive success of the allometric scaling method remained similar with no improvement in prediction irrespective of the correction factor that was employed Applying MLP, brain weight or the rule of exponents as correction factors resulted in no improvement in prediction
65

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 25222534

66

See also Obach & al for the value of allometry as a predictive tool

67

Correction factors for renally and biliary excreted drugs

Renally excreted drugs

Clearance / GFR = aBW b

Biliary excreted drugs

Cl Bile _ flow = aBW B

Cl UDPGT = aBW b
UDPGT=UDP-glucuronyltransferase activity
68

Interspecies scaling of clearance

1. 2. 3. 4. Simple allometry Allometry with various biological correction factors
1. 2. Product of maximum life-span (MLP) and clearance Product of brain weight and clearance

Ratio of clearance and GFR Two-term power equation

1. Incorporation of molecular structure parameters

1. 2. incorporation of in-vitro data in in-vivo clearance Correction for protein binding
69

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:
Log (CLman ) = Log (CLrat ) + Log (Cldog ) + MW + Hydrogen _ bounding + ....

70

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 1. Correction for protein binding 1. incorporation of in-vitro data in in-vivo clearance

71

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
72

Interspecies scaling of clearance

1. 2. 3. 4. 5. 6. Simple allometry Allometry with various biological correction factors
1. 2. Product of maximum life-span (MLP) and clearance Product of brain weight and clearance

Ratio of clearance and GFR Two-term power equation Incorporation of molecular structure parameters Correction for protein binding

1. incorporation of in-vitro data in invivo clearance

73

Dose for an hepatic cleared drug with a low hepatic ER and a total absorption

V max Dose = fu ECtherapeutical Km

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)
74

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

Cl animal

CLhuman ( hepatocytes ) Cl animal ( hepatocytes )

= a BW b

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

75

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 Bosentan: is an orally active, nonpeptide, competitive antagonist of both ETA and ETB (endothelin type A and B) receptors, mainly eliminated by liver metabolism and characterized by a very large interspecies variability
76

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

Cl = a BW b

Clanimal _ in vivo

Clhuman_ hepatocytes Clanimal _ hepatocytes

R2=0.525 Predicted human clearance=196ml/min

R2=0.976 Predicted human clearance=100mL/min 77

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

78

Incorporation of in vitro data in in vivo clearance

Methods Simple allometry CL x Brain Weight In-vitro method Rule of exponent %MAE 164 61 40 38

Data of Lave al (J Pham Sci 1997 86 584-590) on 10 extensively metabolised drugs reanalysd by Mahmood 2005

79

Lav et al: Pharmac Res 1996 13 pp97-101

80

Incorporation of in-vitro data in invivo clearance

Methods Simple allometry CL x Brain Weight In-vitro method Rule of exponent %MAE 164 61 40 38

Data of Lave al (J Pham Sci 1997 86 584-590) on 10 extensively metabolised drugs reanalysd by Mahmood 2005

81

Extrapolation of bioavailability

82

Bioavailability in man:
prediction from rodents, primates & dogs ED%

ED50 =

Clearance x target EC50 Bioavailability

83

Absorption & Bioavailability (F)

%F = fabs (1 fg ) (1 ERH )
where fabs = fraction absorbed from GI lumen fg = fraction metabolized by GI tissue ERH = hepatic extraction ratio, equivalent to hepatic first pass effect

84

Bioavailability in man:
prediction from rodents, primates & dogs

85

From Grass ADDR 2002

In vivo prediction of absolute bioavailability

Correlation coefficient (R2) Man vs rat: 0.4 Man vs dog: 0.3 Man vs primates: 0.2

Caco-2; eversed sac

86

Extrapolation of Vss

87

Interspecies scaling of volumes of distribution (Vd)

Vss = Vp + Vt fup fut

Where Vp, is the volume of plasma; Vt is tissue volume and fup and fut are the fraction of unbound drug in plasma and tissues respectively Usually a change in fut has a greater effect than fup on Vss

88

The minimal volume of distribution is 7.5 L (0.1 L/kg)

VD = 7.5 + 7.5 x fu + 27L x fu p
Volume of distribution of albumin Drug highly bound to No partitioning plasma protein No tissue binding fu=very smal

fuT

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
89

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.
90

Volume of distribution of propranolol

Vtotal Vfree (Unbound)

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)

91

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

92

Extrapolation of half-life

93

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
94

HL

R2=0.14

CL

R2=0.90

R2=0.94 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

95

96

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

97

Age-related changes clearance

Morphine
Fentanyl

98

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)
Mahmood BJCP 2006

99

Tested models
1. Classical allometric equation with different exponents

CLin _ child = Cl adult

BWchild BWadult

0.75 _ or _ 0.80 _ or _ 1.0

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
Mahmood BJCP 2006
100

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
Mahmood BJCP 2006
101

Percent root mean square (RMSE) and percent error in the prediction of clearance in children by several methods
Number of predictions in error (>100%) for 124 predictions

Tested Exponents: 0.75, 0.89, 0.85 and 1.0 L+K: liver and kidney weights correction Mixed : decision tree based upon age

Mahmood BJCP 2006

102

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
Mahmood BJCP 2006
103

Children from 1 to 5 years old

The best approach appears to be the liver and kidney weights corrections

Mahmood BJCP 2006

104

Children >5 years old

One can use any exponent: (0.75, 0.80 or 0.85)

Mahmood BJCP 2006

105

Allometry in veterinary medicine

106

107

108

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
109

Limits of allometic scaling

110

111

Limits of allometric scaling

112

For more information, consult the Mahmood book

113