A Short Course in Pharmacokinetics

Renal excretion

Arterial

supply

(130 ml/min)

Venous

return

Proximal

tubule

Distal

tubule

Loop of Henle

Collecting

tubule

Urine

(1.5l/day)

Glomerulus

E.g. gentamicin, cephalexin

Active secretion

Reabsorption

Click to edit Master title style

March 22, 2005

Christopher Town, Ph.D.

Excretion

Most compounds are excreted in the urine or feces.

parent and metabolites

difficult to quantitate without radiolabel

Some excretion through lungs, in saliva or in sweat,

residues may remain in tissues for extended periods


March 22, 2005


Moving from Animals to Man

Humans and model animals have different biochemistry, physiology and anatomyPredictions of a drugs PK profile in humans using animal PK data must account for these differencesFor example, P450sIsoform distribution varies from species to speciesOrthologous proteins in different species may not be identical and may have different structures and substrate specificitiesAllometric scaling is used to predict differences based only on size.


March 22, 2005


Allometric Scaling

The relationship of some pharmacokinetic parameters across species can be correlated with body weight.One can determine an empirical relationship of the log of the Clearance vs. the log of body weight and log of the volume of distribution vs. the log of body weight.These parameters can be used to extrapolate PK parameters in humans when parameters have been determined in lower species (mouse, rat, dog, monkey, etc.)The relationship is not always predictive, but it can often give a good estimate.


March 22, 2005


Allometric scaling of rat and dog extrapolate human

Sheet1

CL,normCLVss,normVssB.W.

Rat0.180.0450.120.030.25

Dog0.090.9720.33.2410.8

Human0.064.470.4733.0970

CLVssB.W.

Log Value-1.347-1.523-0.602

-0.0120.5111.033

0.6501.5201.845

Sheet2

Sheet3

Allometric Scaling of BAY 76-7179

0.001

0.01

0.1

1

10

100

1000

10000

0.1110100

Body Weight (kg)

CL (l/h)

CL


0.01

0.1

1

10

100

1000

0.1110100

Body Weight (kg)

Vss (l)

Vss

MBD000260E8.xls

Chart3

0.25

10.8

70

CL

Body Weight (kg)

CL (l/h)


0.045

0.972

4.466243145

Sheet1

Column 1

Column 11

Allom

Allometric Scaling of BAY 76-7179 Based on a 2-3 mg/kg IV DoseCl

SUMMARY OUTPUT


Rat0.180.0450.120.030.25Regression Statistics

Dog0.090.9720.33.2410.8Multiple R1

Human0.064.470.4733.0970R Square1

Adjusted R Square65535

Standard Error0

Observations2

CLVssB.W.

Log Value-1.347-1.523-0.602ANOVA

-0.0120.5111.033dfSSMSFSignificance F

0.6501.5201.845Regression10.8903834070.8903834070

Residual02.35926418187436E-3365535

Total10.890383407

CoefficientsStandard Errort StatP-valueLower 95%Upper 95%Lower 95.0%Upper 95.0%

Intercept-0.8555437087065535-0.8555437087-0.8555437087-0.8555437087-0.8555437087

X Variable 10.8159382530655350.8159382530.8159382530.8159382530.815938253

Vss

SUMMARY OUTPUT

Regression Statistics

Multiple R1

R Square1


Standard Error0

Observations2

ANOVA

dfSSMSFSignificance F

Regression12.06740608472.06740608470

Residual06.16297582203915E-3265535

Total12.0674060847


Intercept-0.7743276875065535-0.7743276875-0.7743276875-0.7743276875-0.7743276875

X Variable 11.24331639460655351.24331639461.24331639461.24331639461.2433163946

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Allom

0

0

0

CL

Body Weight (kg)

CL (l/h)


0

0

0

Modeling

0

0

0

Vss

Body Weight (kg)

Vss (l)


0

0

0

Human

00

00

Y

Predicted Y

X Variable 1

Y

X Variable 1 Line Fit Plot

0

0

0

0

Extrapolated PK Parameters

0

0

X Variable 1

Residuals

X Variable 1 Residual Plot

0

0

Sheet5

00

00

Y

Predicted Y

Y


0

0

0

0

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0

0

X Variable 1

Residuals


0

0

Sheet7

00

00

Y

Predicted Y

X Variable 1

Y


0

0

0

0

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0

X Variable 1

Residuals


1

Sheet9

00

00

Y

Predicted Y

X Variable 1

Y


0

1

0

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X Variable 1

Residuals


1

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00

00

Y

Predicted Y

X Variable 1

Y


0

1

0

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MBD00026779.xls

Chart6

0.25

10.8

70

Vss

Body Weight (kg)

Vss (l)


0.03

3.24

33.0912334324

Sheet1

Column 1

Column 11

Allom

Allometric Scaling of BAY 76-7179 Based on a 2-3 mg/kg IV DoseCl

SUMMARY OUTPUT


Rat0.180.0450.120.030.25Regression Statistics

Dog0.090.9720.33.2410.8Multiple R1

Human0.064.470.4733.0970R Square1


Standard Error0

Observations2

CLVssB.W.

Log Value-1.347-1.523-0.602ANOVA

-0.0120.5111.033dfSSMSFSignificance F

0.6501.5201.845Regression10.8903834070.8903834070

Residual02.35926418187436E-3365535

Total10.890383407


Intercept-0.8555437087065535-0.8555437087-0.8555437087-0.8555437087-0.8555437087

X Variable 10.8159382530655350.8159382530.8159382530.8159382530.815938253

Vss

SUMMARY OUTPUT

Regression Statistics

Multiple R1

R Square1


Standard Error0

Observations2

ANOVA

dfSSMSFSignificance F

Regression12.06740608472.06740608470

Residual06.16297582203915E-3265535

Total12.0674060847


Intercept-0.7743276875065535-0.7743276875-0.7743276875-0.7743276875-0.7743276875

X Variable 11.24331639460655351.24331639461.24331639461.24331639461.2433163946

&A

Page &P

Allom

CL

Body Weight (kg)

CL (l/h)


Modeling

Vss

Body Weight (kg)

Vss (l)


Human

Y

Predicted Y

X Variable 1

Y


Extrapolated PK Parameters

X Variable 1

Residuals


Sheet5

Y

Predicted Y

Y


Sheet6

X Variable 1

Residuals


Sheet7

Y

Predicted Y

X Variable 1

Y


Sheet8

1

X Variable 1

Residuals


Sheet9

1

Y

Predicted Y

X Variable 1

Y


Sheet10

1

X Variable 1

Residuals


Sheet11

1

Y

Predicted Y

X Variable 1

Y


Sheet12

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Sheet14

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Sheet16

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March 22, 2005


Acknowledgements

Matthew Prevost

Sandhya Rahematpura

Wolfram Steinke (WBA)

Matthew Bryant

Anita Shah

Paul Adams

Derek Lowe

Michael Boberg

Many web sites where I downloaded images

(h)(ug/l)(h)(ug/l)

000 --

0.1662422.9710.083337700

0.3334435.4440.16628600

0.6667552.2640.33325500

17421.4240.66618100

25572.851115700

42784.17212200

72270.98944200

241046.38872200

30714.68241630

48445.4430932

72108.6348108

965.04672130

9636

Toxicity (22%)

Lack of Efficacy (31%)

Market Reasons (6%)

Poor Biopharmaceutical (PK) Properties (41%)


Rat0.180.0450.120.030.25

Dog0.090.9720.33.2410.8

Human0.064.470.4733.0970

CLVssB.W.

Log Value-1.347-1.523-0.602

-0.0120.5111.033

0.6501.5201.845


0.001

0.01

0.1

1

10

100

1000

10000

0.1110100

Body Weight (kg)

CL (l/h)

CL


0.01

0.1

1

10

100

1000

0.1110100

Body Weight (kg)

Vss (l)

Vss

Rat Plasma Concentration of BAY XX-XXXX after

oral

administration of 5 mg/kg

Time (h)

0

20

40

60

80

100

BAY XX-XXXX (ug/l)

0

2000

4000

6000

8000

BAY XX-XXXX after 2 mg/kg

IV

administration to rats

Time (h)

0

20

40

60

80

100

BAY XX-XXXX (ug/l)

1

10

100

1000

10000

Rat plasma Concentrations of BAY XX-XXXX after

5 mg/kg

oral


Time (h)

0

2

4

6

BAY XX-XXXX (ug/l)

0

2000

4000

6000

8000

BAY XX-XXXX after 2 mg/kg

IV


Time (h)

0

20

40

60

80

100

BAY XX-XXXX (ug/l)

0

10000

20000

30000

Renal excretion

Renal excretion

Arterial

supply

(130 ml/min)

Venous

return

Proximal

tubule

Distal

tubule

Loop of Henle

Collecting

tubule

Urine

(1.5l/day)

Glomerulus

Active secretion

Reabsorption

E.g. gentamicin, cephalexin

P450 isozymes in male rat liver

N. Ohishi et al., Xenobiotica 24, 873-880 (1994)

2A1

2A2

2C6

2C11

2C13

2 E1

3A2

4A1

4A2

4A3

2C7

2B2

N

C

14

O

N

O

O

Area Under the Moment Curve after

Intravenous Administration

Time (h)

0

12

24

36

48

60

72

84

96

Concentration*Time (ug/l*h)

1

10

100

1000

10000

P450 isozymes in human liver

Shimada et al., J. Pharmacol. Exp. Ther. 270, 414-423 (1994)

1A2

2A6

2D6

2 E1

3A

?

2C

2B6

Documents

A Short Course in Pharmacokinetics