$PROBLEM PD DOSERINGSSTUDY EN IV STUDY, PK GEFIXT NAAR PK MODEL
$INPUT NR ID DO STUD AMT RATE EVID TIME DV MDV CMT WT
;$DATA 20100301PRLSIM2.prn
$DATA Simulated_PK_rats.csv IGNORE=@
;IGNORE(STUD.EQ.1)
;IGNORE(ID.EQ.316)
$SUBROUTINE ADVAN9 TOL=3
$MODEL
   COMP=(ABSORB,INITIALOFF) ;IN TOEDIENING, NVT, GEFIXT
   COMP=(ABSORB,INITIALOFF) ;IN TOEDIENING, NVT, GEFIXT
   COMP=(CENTRAL,DEFDOSE);PK PLASMA DATA, GEFIXT
   COMP=(PERIPH) ;PK MICRODIALYSE DATA, GEFIXT
   COMP=(PERIPH) ;PK PERIPHERAL CMT, GEFIXT
   COMP=(PERIPH) ; LACTOTROPH
   COMP=(EFFECT,DEFOBS) ; PK PRL EFFECT VAN REM OP PRL IS DUS DATASET PRL IN MUG/L
$PRIOR  NWPRI
        NTHETA= 19
        NETA= 3
        NEPS= 2
        NTHP= 2
        NETP= 0
        NPEXP=1
$PK
"FIRST
" COMMON/PRCOMG/IDUM1,IDUM2,IMAX,IDUM4,IDUM5
"INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5
"IMAX=10000000
CL3  = THETA(3)   ;L/H PLASMA CMT
V3   = THETA(4)  ;L/KG
Q4   = THETA(5)  ; 4E CMT IS MD CMT
V4   = THETA(6)
Q5   = THETA(7)
V5   = THETA(8)
FK40 = THETA(9)
KA   = THETA(10)
FTOT = THETA(11)
F1   = FTOT*THETA(12)
F2   = FTOT - F1
K24  = THETA(13)/1000
K30 = CL3/V3
K40 = FK40*K30
K34 = Q4/V3
K43 = Q4/V4
K35 = Q5/V3
K53 = Q5/V5
IF(K30.LT.K40) EXIT 1 200
IF(KA.LT.K24) EXIT 1 400
S3 = V3
S4 = V4
;-------------------------------------------  PD ---------------------------------------
IF (STUD.EQ.3) THEN
        STDY = 1
ELSE
        STDY = 0
ENDIF
TBSL    = THETA(14)*(1+THETA(17)*STDY)
BSL    = TBSL*EXP(ETA(1))
;BSL    = THETA(12)*EXP(ETA(1))
K67    = THETA(18)*EXP((ETA(3)))
K70    = THETA(1)
EMAX   = THETA(15)
EC50   = THETA(2)
STDM    = THETA(16)*EXP(ETA(2))
GAMMA  = THETA(19)
STD50  = THETA(20)
A_0(6) = (BSL*K70)/K67
A_0(7) = BSL
KF     = BSL*K70;/(STDM*BSL/(STD50+BSL))
;
ET1 = ETA(1)
ET2 = ETA(2)
ET3 = ETA(3)
;
$DES
DADT(1) = -A(1)*KA  
DADT(2) =           - A(2)*K24
DADT(3) =  A(1)*KA                - A(3)*K34 + A(4)*K43 - A(3)*K35 + A(5)*K53 - A(3)*K30
DADT(4) =             A(2)*K24    + A(3)*K34 - A(4)*K43                       - A(4)*K40 
;-----------------------------------
IF (A(4).GT.0)THEN
CP = (A(4)/V4)
EFF     = 1 + ((EMAX*(CP**GAMMA))/((EC50**GAMMA)+(CP**GAMMA)))
ELSE
CP = 0
EFF = 1
ENDIF
;-----------------------------------
DADT(5) = A(3)*K35 - A(5)*K53      ; de (REM-)concentratie effect relatie wordt omschreven door 
IF (A(7).LT.BSL) THEN                ; een EMAX relatie
  LNA7 = BSL
ELSE
  LNA7 = A(7)
ENDIF
;-----------------------------------
STD     = STDM*(LNA7-BSL);/(STD50+(LNA7-BSL)));/(STDM*BSL/(STD50+BSL));               ; synthese PRL (STD) is afhankelijk van [PRLmicrodial.]=LNA7
KFT     = KF*(1+STD)              ; systeem (PRL-)concentratie effect(synthese) relatie
DADT(6) = KFT - A(6)*K67*EFF        ; wordt omschreven door LOG van A(7); LNA7
DADT(7) =      A(6)*K67*EFF - A(7)*K70
CONC = A(4)/V4
;
$ERROR
IPRED=A(7)
Y = IPRED*(1+EPS(1)) + EPS(2)
IF(IPRED.EQ.0) IPRED=0.0001
IRES = DV-IPRED
IF(IRES.EQ.0) IRES=0.0001
IWRES = IRES/IPRED
;
$THETA 
;Parameters with PRIOR
( 0 , 5.72 , 1000000 ) 
;----------------------------------
( 0 , 0.0804 , 1000000 ) 
;----------------------------------
; PK parameters
1.12 FIX         ;3  CL3 L/H
0.0881 FIX       ;4  V3 L/KG
0.7 FIX          ;5  Q4
0.873 FIX        ;6  V
1.2 FIX          ;7  Q5
0.417 FIX        ;8  V5
0.302 FIX        ;9  FK40, K40=FK40*CL3/V3
1.54 FIX         ;10  KA
0.892 FIX        ;11  FTOT
0.249 FIX        ;12 F1  = FTOT*THETA(10)*EXP(ETA(10))
33.1 FIX         ;13 K24*1000
;----------------------------------
;PD parameters
( 1 , 6.24 , 1000000 ) 
( 0 , 25 , 1000000 ) 
( 0 , 3.74 , 1000000 ) 
( -0.1 ) 
( 0 , 0.8496 , 1000000 ) 
( 1 FIX   )   ; TH19 GAMMA
;( 0 , 12.4 , 1000000 ) 
;
$OMEGA 
0.05           ;1 BSL (BEIDE)
0.0 FIX        ;2 STDM
$OMEGA
0.0 FIX            ;3 EMAX
$SIGMA
0.07              ; CMT7 PROP
8              ; CMT7 ADD
;----------------------------------
;---------------------------------------------------------------------------------------------------------------------
; prior information 
$THETA
(  6    FIX    )   ; TH1
( 0.0419 FIX  )   ; TH2 EC50
;----------------------prior uncertainty for theta -------------------------------------------------------------------
$OMEGA 
0.167  FIX  
0.002584 FIX                       
$EST METHOD=1 INTERACTION ;SLOW;No CWRES
NOABORT MAXEVAL=9999 PRINT=1 SIGDIG=3  POSTHOC ;No CWRES
;$SIM (20100526 NEW) ONLYSIM SUBPROBLEM=250
$COV MATRIX=R COMP
$TABLE ID TIME STUD CMT DO EFF CONC EC50 EMAX GAMMA
PRED BSL ET1 ET2 ET3 STD IPRED IWRES MDV
ONEHEADER NOPRINT 
FILE=J.COMB.EMAX.LIN.FOCE.ETABSL.r.1.par