Population pharm acokinetics Population pharm acokinetics and optim - - PowerPoint PPT Presentation

SLIDE 1

1

Population pharm acokinetics Population pharm acokinetics and optim al design of paediatric and optim al design of paediatric studies for Fam ciclovir studies for Fam ciclovir

Kayode Ogungbenro, I van Mathew s, Leon Aarons School of Pharm acy & Pharm aceutical Sciences The University of Manchester

SLIDE 2

2

Outline Outline

Introduction Aims Data description Method

Modelling Paediatric dose adjustment Optimisation of sampling times and windows Sample size calculations

Results

Modelling Paediatric dose adjustment Optimisation of sampling times and windows Sample size calculations

Conclusion

SLIDE 3

3

I ntroduction I ntroduction

Famciclovir

• rally administered pro-drug of the antiviral agent

penciclovir

little or no parent compound is recovered in blood or

urine

licensed in adults for treatment of herpes zoster and

herpes simplex infections (125 – 750 mg)

PK extensively studied in adults – clinical

success

No population PK analysis has been published Limited information about the PK in paediatrics

Two attempts (post filing) were terminated early –

recruitment issues, probably related to relatively intensive sampling

SLIDE 4

4

Aim s Aim s

To develop a population PK model

Adults and paediatrics (appropriate

covariates)

Design single dose studies in four

paediatrics age groups (1month – 1 yr, 1 - 2 yr, 2 – 5 yr and 5 - 12 yr)

Appropriate dose Limited sampling designs Adequate number of patients

SLIDE 5

5

Data Data

Plasma data from 6 clinical trials was provided

by Novartis (including 2 paediatric studies, a bioavailability and a renal impairment study)

Combined Paediatrics Adults Covariate Mean SD Range Mean SD Range Mean SD Number of subjects 69

• 23
• 46
• Number of
• ccasions

160

• 39
• 121
• Total plasma
• conc. data

1676

• 322
• 1354
• Age (years)

26.5 15.8 2-63 8.1 3.4 2-17 35.8 10.6 20- 63 Weight (kg) 59.3 23.7 13.9- 94.6 29.5 12.2 13.9- 59.8 74.1 9.7 56.4- 94.6 Serum creatinine (mg.dL-1) 0.94 0.33 0.28- 1.94 0.60 0.13 0.28- 0.78 1.10 0.27 0.69- 1.94 Sex (M/F) 62/7

• 17/6
• 45/1
• Creatinine clearance

(mL.min-1) 87.9 34.5 27.6- 175.6 58.2 19.9 27.6- 122.5 102.8 30.4 45.5- 175.6

SLIDE 6

6

Method Method -

• m odelling

m odelling

NONMEM V1 (FOCE/ INTERACTION) 1,2,3 compt first order absorption PK models

were tested

Add, Exp IIV models and add, prop or combined

residual error models were tested

Covariates – difference in obj function and

graphics

An allometric weight model was applied to

volume and clearance parameters

Several age and CRCL models were tested Bootstrap analysis of the final model

SLIDE 7

7

Method Method -

• dose adjustm ent

dose adjustm ent

Simulations

Reference values obtained for weight and

serum creatinine (adults and paediatric age groups) to allow extrapolation of PK model

Dose adjusted to achieve the same AUC and

Cmax as obtained for a 500mg adult dose

SLIDE 8

8

Savory, AnnClinBiochem 1990; 27: 99-101 10 20 30 40 50 60 70 80 90 100 1

• 3

m

• n

t h s 6

• 1

2 m

• n

t h s 2 y e a r s 4 y e a r s 6 y e a r s 8 y e a r s 1 y e a r s 1 2 y e a r s 1 4 y e a r s 1 6 y e a r s 1 8 y e a r s 2 y e a r s Serum creatinine (umole/L)

SLIDE 9

9

Method Method -

• optim isation of sam pling
• ptim isation of sam pling

tim es and w indow s tim es and w indow s

Model based approach – population Fisher

information matrix (PFIM) in MATLAB

Optimisation of sampling times

Modified Fedorov exchange algorithm (grid size 0.25) PFIM evaluated by simultaneous Monte Carlo

integration over covariate distributions (Latin hypercube sampling)

Design region between 0 and 8 hr, single elementary

design and 5 times per patient

Optimisation of sampling windows

Sampling windows around D-optimal time points Assuming 95% mean efficiency level and uniform

sample distribution

SLIDE 10

10

Sam ple size calculations Sam ple size calculations

Determined using simulations in NONMEM

based on confidence interval approach

Power of the final sampling windows

design to estimate 95% confidence interval on the mean of a parameter of choice (CL and V) within specified precision levels

Precision limits – 30, 40 and 50% 200 simulations in NONMEM

(FOCE/ INTERACTION)

SLIDE 11

11

Results Results -

• m odelling

m odelling

Final model – 2 compartment first order

absorption model with lag time

Proportional IIV and exponential residual

error model

Covariates

allometric weight on CL, V1, V2 and Q empirical fractional age model on CL empirical CRCL power model on CL

CLCR

P STD STD AGE AGE STD CL yrs

CLCR CLCR AGE K AGE K WT WT CL ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ − − ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ =

< < <

* * *

40 40 4 3 40

θ

CLCR

P STD STD AGE AGE STD CL yrs

CLCR CLCR AGE K AGE K WT WT CL ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ − − ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ =

≥ ≥ ≥

* * *

40 40 4 3 40

θ

4 3 1 2 1 1

* , * , *

2 1

⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ = ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ = ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ =

STD Q STD V STD V

WT WT Q WT WT V WT WT V θ θ θ

SLIDE 12

12

Results Results -

• m odelling

m odelling

Original data Bootstrap procedure Parameter Estimate CV (%) Estimate CV (%) ka (h-1) 1.86 10.3 1.87 10.7 CL (L.h-1.70kg-1) 31.2 6 31.3 6.27 V1 (L.70kg-1) 28.6 6 28.5 6.19 V2 (L.70kg-1) 54.5 4.9 54.7 5.03 Q (L.h-1.70kg-1) 60.2 7.1 60.3 7.03 F 0.598 2.9 0.598 2.97 T-lag (h) 0.206 2.2 0.206 2.39 KAGE<40 159 37.4

• 40

AGE

K

≥

113 24.4

• exponent of FCLCR

0.28 45.7 0.270 47.9 BSVka 0.640 25.9 0.627 12.8 BSVCL 0.23 22.3 0.220 11.4 BSVV1 0.003 fix

• 0.003 fix

BSVV2 0.255 29.3 0.250 14.8 BSVQ 0.342 59.4 0.331 27.7 Proportional error 0.221 9.6 0.221 4.74 Additive error (mg.L-1) 0.01 fix

• 0.01 fix

SLIDE 13

13

Results Results -

• m odelling

m odelling

Predicted Concentration (mg.L-1) Observed Concentration (mg.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 88 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1313 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 1515 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 35 3535 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 54 54 54 54 54 54 54 54 54 54 54 54 59 59 59 59 59 59 59 59 59 59 59 59 59 60 60 60 60 60 60 60 60 60 60 60 60 61 61 61 61 61 61 61 61 61 61 61 62 62 62 62 62 62 62 62 62 62 62 62 63 63 63 63 63 63 63 63 63 63 63 63 64 64 64 64 64 64 64 64 64 64 64 65 65 65 65 65 65 65 65 65 65 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 67 67 67 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 71 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 72 72 72 72 75 75 75 75 75 75 75 75 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 78 78 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 80 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 103 103 103 103 103 103 103 103 103 103 103 103 103 103 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

Predicted Concentration (mg.L-1) Observed Concentration (mg.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 88 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1313 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 1515 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 35 3535 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 54 54 54 54 54 54 54 54 54 54 54 54 59 59 59 59 59 59 59 59 59 59 59 59 59 60 60 60 60 60 60 60 60 60 60 60 60 61 61 61 61 61 61 61 61 61 61 61 62 62 62 62 62 62 62 62 62 62 62 62 63 63 63 63 63 63 63 63 63 63 63 63 64 64 64 64 64 64 64 64 64 64 64 65 65 65 65 65 65 65 65 65 65 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 67 67 67 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 71 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 72 72 72 72 75 75 75 75 75 75 75 75 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 78 78 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 80 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 103 103 103 103 103 103 103 103 103 103 103 103 103 103 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

A

Predicted Concentration (mg.L-1) Observed Concentration (mg.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 88 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1313 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 1515 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 35 3535 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 54 54 54 54 54 54 54 54 54 54 54 54 59 59 59 59 59 59 59 59 59 59 59 59 59 60 60 60 60 60 60 60 60 60 60 60 60 61 61 61 61 61 61 61 61 61 61 61 62 62 62 62 62 62 62 62 62 62 62 62 63 63 63 63 63 63 63 63 63 63 63 63 64 64 64 64 64 64 64 64 64 64 64 65 65 65 65 65 65 65 65 65 65 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 67 67 67 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 71 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 72 72 72 72 75 75 75 75 75 75 75 75 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 78 78 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 80 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 103 103 103 103 103 103 103 103 103 103 103 103 103 103 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

Predicted Concentration (mg.L-1) Observed Concentration (mg.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 88 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1313 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 1515 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 35 3535 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 54 54 54 54 54 54 54 54 54 54 54 54 59 59 59 59 59 59 59 59 59 59 59 59 59 60 60 60 60 60 60 60 60 60 60 60 60 61 61 61 61 61 61 61 61 61 61 61 62 62 62 62 62 62 62 62 62 62 62 62 63 63 63 63 63 63 63 63 63 63 63 63 64 64 64 64 64 64 64 64 64 64 64 65 65 65 65 65 65 65 65 65 65 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 67 67 67 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 71 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 72 72 72 72 75 75 75 75 75 75 75 75 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 78 78 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 80 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 103 103 103 103 103 103 103 103 103 103 103 103 103 103 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

A Predicted Concentration (mg.L-1) O bserved C

• ncentration (m

g.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 1 10 10 10 1 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 1 2 12 1 2 1 2 12 12 12 12 12 12 12 1 2 12 12 12 13 13 1 3 13 13 13 13 1 3 13 13 13 13 13 1 3 13 13 1 3 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1 3 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 1 4 14 14 1 4 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 1 5 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 1 6 16 16 16 16 16 16 16 1 6 16 1 6 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 1 6 16 16 16 16 1 6 16 16 16 17 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 1 7 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 1 8 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 2 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 20 20 20 20 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 2 2 2 2 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 3 2 32 32 32 3 2 32 32 32 3 2 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 3 3 33 33 33 34 34 3 4 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 3435 3535 35 35 35 3 5 3 5 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 3 6 36 36 36 36 36 36 36 36 36 36 3 6 36 36 3 6 36 36 36 36 36 36 37 37 3 7 37 37 37 37 37 37 37 37 3 7 37 37 37 37 37 3 7 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 3 8 38 38 38 38 38 38 38 38 39 39 39 39 3 9 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 4 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 4 1 41 41 41 41 41 4 1 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 4 2 4 2 42 42 54 54 54 5 4 54 54 54 54 5 4 54 54 54 59 59 59 59 59 59 59 59 59 5 9 59 5 9 59 60 60 60 60 60 6 60 60 60 60 60 6 61 61 61 61 61 61 61 61 61 61 61 62 6 2 62 62 62 62 62 62 62 62 62 62 63 6 3 63 63 63 63 63 6 3 63 6 3 63 6 3 64 64 64 64 6 4 6 4 64 64 64 64 64 65 65 65 6 5 65 65 6 5 65 65 6 5 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 6 7 67 6 7 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 7 1 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 7 2 72 72 72 75 75 75 75 7 5 75 75 75 7 6 76 76 76 76 7 6 76 76 76 76 76 76 76 76 76 76 76 76 7 8 7 8 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 8 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 9 1 91 91 91 91 91 91 91 91 91 91 91 92 9292 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 9 3 93 93 93 9 3 93 93 9 3 93 93 93 93 93 93 93 93 94 9 4 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 9 6 96 96 9 6 96 96 96 9 6 96 96 96 96 96 96 97 97 9 7 9 7 97 97 97 97 9 7 97 97 97 97 97 97 97 97 98 98 98 98 98 98 9 8 98 98 98 9 8 98 98 98 98 98 100 100 100 10 100 1 00 100 100 100 100 10 100 100 100 1 00 10 3 103 103 103 1 03 103 103 103 1 03 103 1 03 1 03 103 103 104 104 104 104 104 104 104 104 104 104 104 104 10 4 104 10 4 104 104 104 1 05 105 105 105 105 105 105 105 1 05 105 1 05 105 10 5 1 05 105 105 105 1 05 107107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 1 07 107 1 08 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

Predicted Concentration (mg.L-1) O bserved C

• ncentration (m

g.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 1 10 10 10 1 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 1 2 12 1 2 1 2 12 12 12 12 12 12 12 1 2 12 12 12 13 13 1 3 13 13 13 13 1 3 13 13 13 13 13 1 3 13 13 1 3 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1 3 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 1 4 14 14 1 4 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 1 5 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 1 6 16 16 16 16 16 16 16 1 6 16 1 6 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 1 6 16 16 16 16 1 6 16 16 16 17 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 1 7 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 1 8 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 2 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 20 20 20 20 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 2 2 2 2 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 3 2 32 32 32 3 2 32 32 32 3 2 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 3 3 33 33 33 34 34 3 4 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 3435 3535 35 35 35 3 5 3 5 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 3 6 36 36 36 36 36 36 36 36 36 36 3 6 36 36 3 6 36 36 36 36 36 36 37 37 3 7 37 37 37 37 37 37 37 37 3 7 37 37 37 37 37 3 7 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 3 8 38 38 38 38 38 38 38 38 39 39 39 39 3 9 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 4 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 4 1 41 41 41 41 41 4 1 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 4 2 4 2 42 42 54 54 54 5 4 54 54 54 54 5 4 54 54 54 59 59 59 59 59 59 59 59 59 5 9 59 5 9 59 60 60 60 60 60 6 60 60 60 60 60 6 61 61 61 61 61 61 61 61 61 61 61 62 6 2 62 62 62 62 62 62 62 62 62 62 63 6 3 63 63 63 63 63 6 3 63 6 3 63 6 3 64 64 64 64 6 4 6 4 64 64 64 64 64 65 65 65 6 5 65 65 6 5 65 65 6 5 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 6 7 67 6 7 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 7 1 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 7 2 72 72 72 75 75 75 75 7 5 75 75 75 7 6 76 76 76 76 7 6 76 76 76 76 76 76 76 76 76 76 76 76 7 8 7 8 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 8 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 9 1 91 91 91 91 91 91 91 91 91 91 91 92 9292 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 9 3 93 93 93 9 3 93 93 9 3 93 93 93 93 93 93 93 93 94 9 4 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 9 6 96 96 9 6 96 96 96 9 6 96 96 96 96 96 96 97 97 9 7 9 7 97 97 97 97 9 7 97 97 97 97 97 97 97 97 98 98 98 98 98 98 9 8 98 98 98 9 8 98 98 98 98 98 100 100 100 10 100 1 00 100 100 100 100 10 100 100 100 1 00 10 3 103 103 103 1 03 103 103 103 1 03 103 1 03 1 03 103 103 104 104 104 104 104 104 104 104 104 104 104 104 10 4 104 10 4 104 104 104 1 05 105 105 105 105 105 105 105 1 05 105 1 05 105 10 5 1 05 105 105 105 1 05 107107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 1 07 107 1 08 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

B

Predicted Concentration (mg.L-1) O bserved C

• ncentration (m

g.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 1 10 10 10 1 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 1 2 12 1 2 1 2 12 12 12 12 12 12 12 1 2 12 12 12 13 13 1 3 13 13 13 13 1 3 13 13 13 13 13 1 3 13 13 1 3 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1 3 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 1 4 14 14 1 4 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 1 5 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 1 6 16 16 16 16 16 16 16 1 6 16 1 6 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 1 6 16 16 16 16 1 6 16 16 16 17 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 1 7 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 1 8 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 2 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 20 20 20 20 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 2 2 2 2 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 3 2 32 32 32 3 2 32 32 32 3 2 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 3 3 33 33 33 34 34 3 4 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 3435 3535 35 35 35 3 5 3 5 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 3 6 36 36 36 36 36 36 36 36 36 36 3 6 36 36 3 6 36 36 36 36 36 36 37 37 3 7 37 37 37 37 37 37 37 37 3 7 37 37 37 37 37 3 7 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 3 8 38 38 38 38 38 38 38 38 39 39 39 39 3 9 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 4 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 4 1 41 41 41 41 41 4 1 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 4 2 4 2 42 42 54 54 54 5 4 54 54 54 54 5 4 54 54 54 59 59 59 59 59 59 59 59 59 5 9 59 5 9 59 60 60 60 60 60 6 60 60 60 60 60 6 61 61 61 61 61 61 61 61 61 61 61 62 6 2 62 62 62 62 62 62 62 62 62 62 63 6 3 63 63 63 63 63 6 3 63 6 3 63 6 3 64 64 64 64 6 4 6 4 64 64 64 64 64 65 65 65 6 5 65 65 6 5 65 65 6 5 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 6 7 67 6 7 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 7 1 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 7 2 72 72 72 75 75 75 75 7 5 75 75 75 7 6 76 76 76 76 7 6 76 76 76 76 76 76 76 76 76 76 76 76 7 8 7 8 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 8 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 9 1 91 91 91 91 91 91 91 91 91 91 91 92 9292 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 9 3 93 93 93 9 3 93 93 9 3 93 93 93 93 93 93 93 93 94 9 4 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 9 6 96 96 9 6 96 96 96 9 6 96 96 96 96 96 96 97 97 9 7 9 7 97 97 97 97 9 7 97 97 97 97 97 97 97 97 98 98 98 98 98 98 9 8 98 98 98 9 8 98 98 98 98 98 100 100 100 10 100 1 00 100 100 100 100 10 100 100 100 1 00 10 3 103 103 103 1 03 103 103 103 1 03 103 1 03 1 03 103 103 104 104 104 104 104 104 104 104 104 104 104 104 10 4 104 10 4 104 104 104 1 05 105 105 105 105 105 105 105 1 05 105 1 05 105 10 5 1 05 105 105 105 1 05 107107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 1 07 107 1 08 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

Predicted Concentration (mg.L-1) O bserved C

• ncentration (m

g.L

• 1)

2 4 6 8 10 2 4 6 8 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 1 10 10 10 1 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 1 10 10 10 10 10 10 10 10 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 1 1 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 1 2 12 1 2 1 2 12 12 12 12 12 12 12 1 2 12 12 12 13 13 1 3 13 13 13 13 1 3 13 13 13 13 13 1 3 13 13 1 3 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 1 3 13 13 13 13 13 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 1 4 14 14 1 4 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 1 5 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 16 16 1 6 16 16 16 16 16 16 16 1 6 16 1 6 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 1 6 16 16 16 16 1 6 16 16 16 17 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 1 7 17 17 17 1 7 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 1 8 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 1 9 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 2 20 20 20 20 20 20 20 20 20 20 20 20 2 20 20 20 20 20 20 20 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 21 21 21 21 21 21 21 2 1 2 1 21 21 21 21 21 22 22 22 22 22 22 22 22 22 22 22 22 2 2 2 2 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 22 22 22 22 22 22 2 2 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 23 23 23 23 23 23 23 23 2 3 23 23 2 3 23 23 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 3 2 32 32 32 3 2 32 32 32 3 2 32 32 32 32 32 32 32 32 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 3 3 33 33 33 34 34 3 4 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 3435 3535 35 35 35 3 5 3 5 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 3 6 36 36 36 36 36 36 36 36 36 36 3 6 36 36 3 6 36 36 36 36 36 36 37 37 3 7 37 37 37 37 37 37 37 37 3 7 37 37 37 37 37 3 7 37 37 37 37 37 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 3 8 38 38 38 38 38 38 38 38 39 39 39 39 3 9 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 40 40 40 40 40 40 40 4 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 41 4 1 41 41 41 41 41 4 1 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 4 2 4 2 42 42 54 54 54 5 4 54 54 54 54 5 4 54 54 54 59 59 59 59 59 59 59 59 59 5 9 59 5 9 59 60 60 60 60 60 6 60 60 60 60 60 6 61 61 61 61 61 61 61 61 61 61 61 62 6 2 62 62 62 62 62 62 62 62 62 62 63 6 3 63 63 63 63 63 6 3 63 6 3 63 6 3 64 64 64 64 6 4 6 4 64 64 64 64 64 65 65 65 6 5 65 65 6 5 65 65 6 5 65 65 66 66 66 66 66 66 66 66 66 66 66 66 66 6 7 67 6 7 67 67 67 67 67 67 67 67 67 68 68 68 68 68 68 68 68 68 68 68 7 1 71 71 71 71 71 71 71 71 71 72 72 72 72 72 72 7 2 72 72 72 75 75 75 75 7 5 75 75 75 7 6 76 76 76 76 7 6 76 76 76 76 76 76 76 76 76 76 76 76 7 8 7 8 78 78 78 78 78 78 78 79 79 79 79 79 79 79 79 79 79 79 79 79 80 80 8 80 80 80 80 81 81 81 81 81 81 81 82 82 82 82 82 82 82 82 82 91 91 91 9 1 91 91 91 91 91 91 91 91 91 91 91 92 9292 92 92 92 92 92 92 92 92 92 92 92 92 92 92 93 9 3 93 93 93 9 3 93 93 9 3 93 93 93 93 93 93 93 93 94 9 4 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 96 96 9 6 96 96 9 6 96 96 96 9 6 96 96 96 96 96 96 97 97 9 7 9 7 97 97 97 97 9 7 97 97 97 97 97 97 97 97 98 98 98 98 98 98 9 8 98 98 98 9 8 98 98 98 98 98 100 100 100 10 100 1 00 100 100 100 100 10 100 100 100 1 00 10 3 103 103 103 1 03 103 103 103 1 03 103 1 03 1 03 103 103 104 104 104 104 104 104 104 104 104 104 104 104 10 4 104 10 4 104 104 104 1 05 105 105 105 105 105 105 105 1 05 105 1 05 105 10 5 1 05 105 105 105 1 05 107107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 1 07 107 1 08 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

B

Time (h) Weighted Residual 0.5 1.0 5.0 10.0 50.0 100.0

• 5

5

A

Time (h) Weighted Residual 0.5 1.0 5.0 10.0 50.0 100.0

• 5

5

A

Predicted Conc (mg/L) Weighted Residual 1 2 3 4 5 6

• 5

5

B

Predicted Conc (mg/L) Weighted Residual 1 2 3 4 5 6

• 5

5

B

SLIDE 14

14

Results Results -

• m odelling

m odelling

Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 250 mg po

Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 250 mg po

adults and paediatrics Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 250 mg po

Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 250 mg po

adults and paediatrics Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 500 mg po

Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 500 mg po

adults and paediatrics Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 500 mg po

Time (h) Concentration (mg.L-1)

2 4 6 8 10 2 4 6 8 10

DOSE = 500 mg po

adults and paediatrics

10 20 30 40 50 60 70 10 20 30 40 50 60 70 Adults and paedaitrics Age (years) Clearance (L/hr)

B

2 4 6 8 10 12 14 16 18 10 20 30 40 50 60 70 P aediatrics Age (years) Clearance (L/hr)

A

SLIDE 15

15

Results Results – – dose adjustm ent dose adjustm ent

10mg/ kg gave the best AUC ratio and Cmax ratio

2 4 6 8 2 4 6 8 Age Group 1 (0.083 - 1 yr) time (hr) concentration (mg/L ) 2 4 6 8 2 4 6 8 Age Group 2 (1 - 2 yr) time (hr) concentration (mg/L ) 2 4 6 8 2 4 6 8 Age Group 3 (2 - 5 yr) time (hr) concentration (mg/L ) 2 4 6 8 2 4 6 8 Age Group 4 (5 - 12 yr) time (hr) concentration (mg/L )

AUC ratio= 1 .0 5 Cm ax ratio= 0 .9 1 AUC ratio= 1 .0 8 Cm ax ratio= 0 .9 3 AUC ratio= 1 .1 3 Cm ax ratio= 0 .9 5 AUC ratio= 1 .1 8 Cm ax ratio= 1 .0 4

dashed= adults, continuous= paediatrics

SLIDE 16

16

Results Results – – sam pling tim es and sam pling tim es and w indow s optim isation w indow s optim isation

Windows very close in all age groups High sensitivity (narrow window) with window 1 Overlap between windows 2 and 3 New single sampling windows for all paediatrics: 0.25 – 0.4,

0.5 – 1, 1.25 – 1.75, 2.75 – 3.5 and 7.25 – 8 hr

Final windows – 85% efficient for all paediatric age groups

Age Groups Sampling Properties Sample Number 1 2 3 4 1 0.25 0.25 0.25 0.25 2 0.65 0.70 0.70 0.85 3 1.35 1.35 1.30 1.00 4 3.15 3.05 3.00 2.80 Optimal Sampling Times (hr) 5 8.00 8.00 8.00 8.00 1 0.25 - 0.28 0.25 - 0.28 0.25 - 0.28 0.25 - 0.27 2 0.53 - 0.78 0.58 - 0.82 0.58 - 0.82 0.62 - 1.08 3 0.93 - 1.77 0.70 - 2.00 0.66 - 1.94 0.26 - 1.73 4 2.41 - 3.89 2.47 - 3.63 2.48 - 3.52 2.61 - 2.99 Optimal Sampling Windows (hr) 5 7.37 - 8.00 7.45 - 8.00 7.48 - 8.00 7.78 - 8.00

SLIDE 17

17

Results Results – – sam ple size calculations sam ple size calculations

10 20 30 40 50 60 70 80 90 100

Sample Size

30% 40% 50% 10 20 30 40 50 60 70 80 90 100

Sample Size

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Power

30% 40% 50% 10 20 30 40 50 60 70 80 90 100

Sample Size

30% 40% 50% 10 20 30 40 50 60 70 80 90 100

Sample Size

0.1 0.2 0.3 0.4

Power

30% 40% 50% 10 20 30 40 50 60 70 80 90 100

Sample Size

30% 40% 50% 10 20 30 40 50 60 70 80 90 100

Sample Size

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Power

30% 40% 50% 10 20 30 40 50 60 70 80 90 100

Sample Size

30% 40% 50% 10 20 30 40 50 60 70 80 90 100

Sample Size

0.1 0.2 0.3 0.4

Power

30% 40% 50%

Based on V1 Final criterion –

80% power and 40% precision limits

30 patients for

each age groups (120 in total)

Final sample size -

SE(% ) for ka, CL, V1, V2, Q is 25, 5, 25, 10 and 26

SLIDE 18

18

Conclusion Conclusion

A population PK model for adults and paediatrics has

been described

Adult clearance and total volume of distribution

values are comparable to published values from non- compartmental analysis

Age and CRCL in addition to weight are needed to

explain the IIV on clearance

There is a need for dose adjustment in paediatrics

and 10mg/ kg weight is adequate based on simulation

An important area of application of optimal design is

paediatric population (limited sampling - ethical and practical constraint) – help to define only the important sampling times

Future famciclovir paediatric studies using

appropriate dose, limited sampling designs and adequate number of subject have been determined