$PROB PK Modeling MK3475 (2-CMT + MM)
$INPUT PART ID AMT RATE TIME DV OCC EVID MDV 
       DOSE BW RESP PosPre LDV ICL IV1 IV2 IQ IKM IVM 
       ET8 ET9 ET10 LCMT PER
$DATA  ../../Data/PKPD/PDpartIOVbis.csv  IGNORE=# IGN=(PosPre.EQ.1)
$SUB   ADVAN6 TOL=5
$ABBREVIATED DERIV2=NO 
    
$MODEL
       COMP=(CENTRAL)
       COMP=(PERI)
             
$PK 
;***PK PARAMETERS***
OC1 = 0
OC2 = 0
OC3 = 0


IF (PER.EQ.1) OC1 = 1
IF (PER.EQ.2) OC2 = 1
IF (PER.EQ.3) OC3 = 1


OCC1 = OC1*ET8
OCC2 = OC2*ET9
OCC3 = OC3*ET10

AOV = OCC1 + OCC2 + OCC3

CL= ICL 


V1=IV1 


Q=IQ


V2=IV2 


Q=IQ

KM = IKM

VM = IVM

F1 = 1*EXP(0+AOV)

;***PD PARAMETERS***
EMAX = EXP(THETA(1))*EXP(ETA(1))
BASE = EXP(THETA(2))*EXP(ETA(2))
EC50 = EXP(THETA(3))*EXP(ETA(3))
GAM  = EXP(THETA(4))*EXP(ETA(4))

S1=V1

;CALCULATE TIME AFTER DOSE
 IF(NEWIND.NE.2) TDOS=0
 IF(AMT.GT.0) TDOS=TIME
 TAD=TIME-TDOS         ; TIME RELATIVE TO DOSE



$DES
KEL     = CL/V1
K12     = Q/V1
K21     = Q/V2

DADT(1) = - KEL*A(1) - K12*A(1) + K21*A(2) - VM*(A(1)/S1)/(KM+(A(1)/S1)) 
DADT(2) =   K12*A(1) - K21*A(2)


$ERROR CALLFL=0     ; Evaluation for evid=0 only
CP=A(1)/S1
IPRE = EMAX-(EMAX-BASE)*(CP**GAM/(EC50**GAM+CP**GAM))
Y = IPRE*(1+EPS(1))


$THETA
(0.1,0.5,10)
(-1,-0.1,5)
(-1,-0.5,-0.05)
0 FIX

$OMEGA
0.5
0 FIX
0 FIX
0 FIX

$SIGMA
0.1

$EST MSF=msfo12 MAX=9990 NSIGDIG=3 PRINT=5 NOABORT METHOD=1
$COV PRINT=E 
$TABLE ID TIME TAD DOSE CWRES CP IPRE            ONEHEADER NOPRINT FILE=sdtab12