S5. Model code for methotrexate

;; 1. Based on: 
;; 2. Description: Methotrexaxte,final rat PBPK model

$SIZE LTH=100
$PROBLEM rat PBPK for Methotrexate
$INPUT ID DROP DO BLOCK AMT RATE EVID DROP CMT TIME DV MDV WT DROP STUD MDV1
$DATA MTX_PBPK3.csv IGNORE=@

$SUBROUTINE ADVAN8 TOL=2
$MODEL
; 1.  plasma
; 2.  periphery 1
; 3.  periphery 2
; 4.  Brain ECF
; 5.  Brain tissue
; 6.  Brain ICF
; 7.  lysosome
; 8.  CSFLV
; 9.  CSFTFV
; 10. CSFCM
; 11. CSFSAS
; 12. Brain MV

COMP = (CENTRAL,DEFDOSE)  ; plasma
COMP = (PERIPH1)           ; periphery 1 
COMP = (PERIPH2)          ; periphery 2
COMP = (BECF)             ; Brain ECF
COMP = (BT)               ; Brain tissue
COMP = (BICF)             ; Brain ICF
COMP = (Blyso)            ; lysosome 
COMP = (CSFLV)            ; CSFLV 
COMP = (CSFTFV)           ; CSFTFV
COMP = (CSFCM)            ; CSFCM
COMP = (CSFSAS)           ; CSFSAS 
COMP = (BMV)              ; Brain MV  

$PK
CL10     =THETA(1)*EXP(ETA(1))
Q12      =THETA(2)
Q13      =THETA(3)*EXP(ETA(2))
TPA      =THETA(4)
PPA      =THETA(13)
SABBB    =THETA(5)
SABC     =THETA(6)
SABCSFB1 =THETA(7)
SABCSFB2 =THETA(8)
SALYSO   =THETA(9)
QCSF     = 0.0022
QECF     = 0.0002

V1       = THETA(10)*EXP(ETA(3))
V2       = THETA(11)
V3       = THETA(12)
V7       = 0.018
V6       = 1.44
V5       = 1.88
V4       = 0.29
V8       = 0.05
V9       = 0.05
V10      = 0.017
V11      = 0.180
V12      = 0.06

K10      =CL10/V1
K12      =Q12/V1
K21      =Q12/V2
K13      =Q13/V1
K31      =Q13/V3
K411     =QECF/V4
K89      =QCSF/V8
K910     =QCSF/V9
K1011    =QCSF/V10
K111     =QCSF/V11

PHF1=1.3
PHF2=1.3
PHF3=1.3
PHF4=1.3
PHF5=2.5
PHF6=2.5
PHF7=250.0
AF11=1
AF12=46445.5
AF21=1
AF22=46353.1
AF31= 1
AF32=1028201
BF =1
QCBF=1.2


$DES
REPI=IREP
C1=A(1)/V1
C2=A(2)/V2
C3=A(3)/V3
C4=A(4)/V4*BF
C5=A(5)/V5
C6=A(6)/V6
C7=A(7)/V7
C8=A(8)/V8
C9=A(9)/V9
C10=A(10)/V10
C11=A(11)/V11
C12=A(12)/V12


DADT(1)  =  -K12*A(1)+K21*A(2) -K13*A(1)+K31*A(3) -K10*A(1)-QCBF*C1+QCBF*C12
DADT(2)  =   K12*A(1)-K21*A(2)
DADT(3)  =   K13*A(1)-K31*A(3)
DADT(4)  =  -(0.5*TPA*0.998*SABBB*AF12+PPA*0.00006*SABBB)*PHF1*C4/BF+(0.5*TPA*0.998*SABBB*AF11+PPA*0.00006*SABBB)*C12-TPA*SABC*PHF4*C4/BF+TPA*SABC*C6*PHF5-QECF*C4/BF
DADT(5)  =   0
DADT(6)  =  -TPA*SALYSO*PHF6*C6+TPA*SALYSO*C7*PHF7+TPA*SABC*PHF4*C4/BF-TPA*SABC*C6*PHF5
DADT(7)  =   TPA*SALYSO*PHF6*C6-TPA*SALYSO*C7*PHF7
DADT(8)  =   (0.5*TPA*0.998*SABCSFB1*AF21+PPA*0.00016*SABCSFB1)*C12-(0.5*TPA*0.998*SABCSFB1*AF22+PPA*0.00016*SABCSFB1)*PHF2*C8+QECF*C4/BF-QCSF*C8
DADT(9)  =   (0.5*TPA*0.998*SABCSFB2*AF31+PPA*0.00016*SABCSFB2)*C12-(0.5*TPA*0.998*SABCSFB2*AF32+PPA*0.00016*SABCSFB2)*PHF3*C9+QCSF*C8-QCSF*C9
DADT(10) =   QCSF*C9-QCSF*C10
DADT(11) =   QCSF*C10-QCSF*C11
DADT(12) =  -(0.5*TPA*0.998*SABBB*AF11+PPA*0.00006*SABBB)*C12+(0.5*TPA*0.998*SABBB*AF12+PPA*0.00006*SABBB)*PHF1*C4/BF -(0.5*TPA*0.998*SABCSFB1*AF21+PPA*0.00016*SABCSFB1)*C12+(0.5*TPA*0.998*SABCSFB1*AF22+PPA*0.00016*SABCSFB1)*PHF2*C8-(0.5*TPA*0.998*SABCSFB2*AF31+PPA*0.00016*SABCSFB2)*C12+(0.5*TPA*0.998*SABCSFB2*AF32+PPA*0.00016*SABCSFB2)*PHF3*C9+QCSF*C11+QCBF*C1-QCBF*C12


$ERROR 
PL  = (A(1)/V1)
ECF = (A(4)/V4)
LV  = (A(8)/V8)
CM  = (A(10)/V10)

IF(CMT.EQ.1)   IPRED = PL
IF(CMT.EQ.4)   IPRED = ECF
IF(CMT.EQ.8)   IPRED = LV
IF(CMT.EQ.10)  IPRED = CM
IF(IPRED.EQ.0) IPRED=0.001
IRES  = DV-IPRED
IWRES = IRES/IPRED
IF(CMT.EQ.1)  Y = PL*(1+EPS(1))+EPS(5)  
IF(CMT.EQ.4)  Y = ECF*(1+EPS(2))  
IF(CMT.EQ.8)  Y = LV*(1+EPS(3))  
IF(CMT.EQ.10) Y = CM*(1+EPS(4))  


$THETA 
8.04 FIX 
28.5 FIX 
3.33 FIX  
0.00000061 FIX  
263  FIX   
3000 FIX     
12.5 FIX   
12.5 FIX     
1440 FIX 
28.0 FIX     
111  FIX   
83.5 FIX   
5.6  FIX 


$OMEGA 
0.140  FIX    
0.181  FIX   
0.163  FIX   


$SIGMA 
0.0228 FIX
0 FIX  
0 FIX  
0 FIX  
5400 FIX 


$SIMULATION (201105029) ONLYSIM SUBPROBLEMS=200
$TABLE ID DO BLOCK AMT RATE EVID CMT TIME DV MDV WT IPRED PRED RES WRES CWRES REPI STUD MDV1 NOPRINT ONEHEADER
FILE=sdtabMTX_final