$SIZES LIM6=1500 
$PROBLEM MIP COVARIATE MODEL, TREATMENT AFFECTS MARGINATION AND DEMARGINATION.

$INPUT STUDY ID TIME CP=DV DOSE=AMT RATE DURATION CMT EVID MDV CENS YTYPE TYPE DBY DRUG DCH DTYP 
       BIO V2 ADA KE VM KM KA K23 K32 MTT ANC WT DVVSE ORDER PCTCH RATIO PCMT TREATMENTN STRATA DVL=DROP LIMIT=DROP

$DATA "../DA/D8806002.DAS" WIDE IGNORE=# 
$SUBROUTINES  ADVAN14  TOL=9    

$MODEL COMP=(INJ) 
       COMP=(BLOOD) 
       COMP=(AUC)
       COMP=(TISSUE)
       COMP=(RT1) COMP=(RT2) COMP=(RT3) 
       COMP=(PD1) COMP=(PD2) COMP=(PD3) 
       COMP=(PD4) COMP=(PD5) 

$THI
  THETA=LOG(THETAI(1:6))
$THR
  THETAR=EXP(THETA(1:6)) 

$PK
  MU_1  =THETA(1)
  MU_2  =THETA(2)
  MU_3  =THETA(3)
  MU_4  =THETA(4)
  MU_5  =THETA(5)

  MU_6  =THETA(6)
  MU_7  =THETA(7)
  MU_8  =THETA(8)
  MU_9  =THETA(9)

  INDI = DRUG-1

  KTR  = 4/MTT

  F1   = BIO
 
  KOUT = 0.877
 
  S2=V2    

  BETA_ANConA80 = DEXP((MU_7+ETA(7))*DLOG(ANC/4.75))
  A80           = DEXP(MU_1+ETA(1))*BETA_ANConA80  

  BETA_ANConB = DEXP((MU_9+ETA(9))*DLOG(ANC/4.75))
  B    = DEXP(MU_2+ETA(2))*BETA_ANConB

  GA   = DEXP(MU_3+ETA(3))
  D890 = DEXP(MU_4+ETA(4))
  KTRN = DEXP(MU_5+ETA(5))

  D980 = D890

  BETA_DRGonEC50 = DEXP((MU_8+ETA(8))*INDI)
  EC50           = DEXP(MU_6+ETA(6))*BETA_DRGonEC50

  KIN = A80*KOUT*(D890+D980+KOUT)/(D980+KOUT)

  A_0(1)  = 0
  A_0(2)  = 0
  A_0(3)  = 0
  A_0(4)  = 0
  A_0(5)  = 0
  A_0(6)  = 0
  A_0(7)  = 0
  A_0(8)  = A80
  A_0(9)  = A80*D890/(D980+KOUT)
  A_0(10) = KIN/KTRN
  A_0(11) = KIN/KTRN
  A_0(12) = KIN/KTRN


$ERROR
  CALLFL=0
  IPRE    = F
  SIG     = THETA(10)
  LNDV    = DLOG(DV)
  LNIPRE  = DLOG(IPRE)
  DV01    =(LNDV-LNIPRE)/SIG
  LNSIG   = DLOG(SIG)
  LNLOQ   = DLOG(0.078)
  

  LL2 = DV01*DV01 + 2*(LNDV + LNSIG) + 1.837876
  Y  = LL2

  IPRED=IPRE
  IWRES=DV01                

$DES
  IND=DTYP
  DADT(1) =-KTR*A(1)*IND                                                            
  DADT(2) =-A(2)*KE-K23*A(2)+K32*A(4)+KA*A(7)*IND-A(2)*VM/(KM+A(2)/V2)              
  DADT(3) = A(2)/V2                                                                 
  DADT(4) = K23*A(2)-K32*A(4)   

  DADT(5) =-KTR*A(5) +KTR*A(1)
  DADT(6) =-KTR*A(6) +KTR*A(5)
  DADT(7) =-KA *A(7) +KTR*A(6)

  C2      = A(2)/V2

  mult = (1 + B*C2/(EC50+C2))
  D89 = D890*mult
  D98 = D980/mult


  DADT(8) =-D89*A(8) + D98*A(9)     + KTRN*A(12) - KOUT*A(8)
  DADT(9) = D89*A(8) - D98*A(9)                  - KOUT*A(9) 

  DADT(10)=-KTRN*A(10)   + KIN*(A80/A(8))**GA
  DADT(11)=-KTRN*A(11)   + KTRN*A(10)
  DADT(12)=-KTRN*A(12)   + KTRN*A(11)    


  A1 =A(1)
  A2 =A(2)/V2
  A3 =A(3)
  A4 =A(4)
  A5 =A(5)
  A6 =A(6)
  A7 =A(7)
  A8 =A(8)
  A9 =A(9)
  A10=A(10)

 
  CHANGE = A8-A80
  PCTCHANGE = CHANGE/A80*100


$THETA (1E-5,4.02,100)      ; POP_A80
$THETA (0.03,1.22,100)      ; POP_B 
$THETA (0.01,2.0,100)       ; POP_GA 
$THETA (1E-5,1.80,100)      ; POP_D890 
$THETA (1E-4,0.248,100)     ; POP_KTRN

$THETA (0.01,0.216,100)     ; POP_EC50  
$THETA (-100,0.81,100)      ; POP_BETA_ANConA80 
$THETA (-100,1.56,100)      ; POP_BETA_DRGonEC50 
$THETA (-100,0.5,100)       ; POP_BETA_ANConB 
$THETA (0.00001,0.244,10)   ; POP_SD1


$OMEGA DIAGONAL(2)  0.0133                            ; ETA_A80
                    0.919                             ; ETA_B

$OMEGA DIAGONAL(7) 0 FIX                              ; ETA_GA
                   0 FIX                              ; ETA_D890
                   0 FIX                              ; ETA_KTRN
                   0 FIX                              ; ETA_EC50
                   0 FIX                              ; ETA_BETA_ANConA80
                   0 FIX                              ; ETA_BETA_DRGonEC50
                   0 FIX                              ; ETA_BETA_ANConB


$EST NOABORT PRINT=1 NBURN=3000 NITER=500 CONSTRAIN=7
  METHOD=SAEM  POSTHOC ;INTERACTION  
  CTYPE=3 CINTERVAL=10 
  LAPLACIAN GRD=TG(1-9):TS(10) DERCONT=1 -2LL
  SIGL=8 SIGLO=8

$EST METHOD=IMP EONLY=1 ISAMPLE=1000 NITER=20 MAPITER=0

$COV MATRIX=R PRINT=E UNCONDITIONAL