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Table 1 Initial, final, and fixed parameters for CNM

From: Estimation of feasible solution space using Cluster Newton Method: application to pharmacokinetic analysis of irinotecan with physiologically-based pharmacokinetic models

a Parameters Fixed

   
 

Dose

µg/kg

1500

 
 

Duration of infusion

Min

90

 
 

Qliver

ml/min/kg

20.7

 
 

Vliver

ml/kg

24.1

 

b Parameters to estimate

   

ID

  

min

Max

1-5

Kp,liver

-

0.1

10

6-11

CLr

ml/min/kg

1

100

11-15

CLbile

ml/min/kg

1

100

16

CLCES,1

ml/min/kg

1

100

17

CLCES,2

ml/min/kg

1

100

18

CL3A4,1

ml/min/kg

1

100

19

CL3A4,2

ml/min/kg

1

100

20

CLUGT

ml/min/kg

1

100

21-25

kfeces

/min/kg

0.001

0.1

26-30

ka

/min/kg

0.001

0.1

31-35

kLI

/min/kg

0.001

0.1

36-40

ktransit

/min/kg

0.001

0.1

41-45

CL12

ml/min

1

100

46-50

k21

min-1

0.1

10

51-55

Vrapid

ml/kg

10

1000

56*

CLbile,T-tube/CLbile,transit

-

0.1

10

We used the same initial ranges for these parameters in irinotecan and the metabolites

* Fixed and set to be zero when analyzing the OC group.

  

c Objective values

   

ID

  

OC

BDC

1

Urinary accumulation µg/kg

irinotecan

427

412

2

 

SN-38

8.20

17.0

3

 

SN-38G

57.6

227

4

 

NPC

2.67

1.70

5

 

APC

42.5

146

6

Fecal accumulation µg/kg

irinotecan

616

118

7

 

SN-38 + SN-38G

162

52.6

8

 

NPC

25.9

6.05

9

 

APC

158

31.4

10

Biliary accumulation µg/kg

irinotecan

-

349

11

 

SN-38

-

8.32

12

 

SN-38G

-

50.5

13

 

NPC

-

5.68

14

 

APC

-

73.8

  1. a fixed parameters for calculation, b initial parameters to estimate, and c objective values are shown. Minimum and maximum values of the initial ranges were represented for the parameters to estimate. We used the same initial ranges for each of the five parameters for irinotecan and the metabolites, except for #16-20 and #56. We used the same parameter value of #56 for irinotecan and the metabolites. Parameter #56 was fixed and set to be zero and fixed when analyzing the OC group. The total amount of urinary, fecal, and biliary accumulation was normalized to the amount of dose (1500 µg/kg). BDC, bile-duct cancer patients; CL12, clearance from a rapid to a late equilibrium compartments; CLCES,1, metabolic clearance of irinotecan by CES2 to form SN-38; CLCES,2, metabolic clearance of NPC by CES2 to form SN-38; CLbile,total, sum of biliary clearance to a transit compartment and biliary clearance to biliary T-tube; CL3A4,1, metabolic clearance of irinotecan by CYP3A4 to form APC; CL3A4,2, metabolic clearance of irinotecan by CYP3A4 to form NPC; CLR, renal clearance; CLUGT, metabolic clearance of SN-38 by UGT to form SN-38G; k21, kinetic constant from a late to a rapid equilibrium compartment; ka, absorption rate constant; kfeces, kinetic constant for the transit from large intestine to feces; kLI, kinetic constants for the transit from small intestine to large intestine; KP,H, concentration ratio between liver and rapid equilibrium compartment; ktransit, kinetic constant for the transit in bile compartments to small intestine; OC, other cancer patients; QH, blood flow rate in liver; VH, volume of a liver; Vrapid, apparent volume of a rapid equilibrium compartment.