$PROBLEM  Baricitinib  Population PKPD Analysis  RUN=002
$INPUT PROJ,ID,AGEE,GEN,AMT,TIME,EVID,MDV,FLAG,DV,RATE,CMT
  ;FLAG 5 = RET
  ;FLAG 6 = RBC
  ;FLAG 7 = Hb

$DATA data.csv IGNORE=C 

$SUBROUTINE ADVAN13 TRANS1 TOL=5

$MODEL
COMP=(CENTRAL,DEFDOSE,DEFOBS)
COMP=(PERIPH)
COMP=(PROL)   ; pregenitor cell pool
COMP=(TRAN1)  ; transit 1
COMP=(TRAN2)  ; transit 2
COMP=(TRAN3)  ; transit 3
COMP=(CIRC)   ; circulating RET
COMP=(TRAN4)  ; transit 4
COMP=(TRAN5)  ; transit 5
COMP=(TRAN6)  ; transit 6
COMP=(CIRC2)  ; circulating RBC
COMP=(TRAN7)  ; transit 7
COMP=(TRAN8)  ; transit 8
COMP=(TRAN9)  ; transit 9
COMP=(Hb)     ; Hb

$PK
   ....
   K10=CL/V1
   K12=Q/V1
   K21=Q/V2

   AVAL=AGEE-48
   IF (AGEE.EQ.0) AVAL=0
   I5=0
   IF (GEN.EQ.1) I5=1
  
   TVBASE=THETA(1)*EXP(AVAL*THETA(15))*(1+I5*THETA(17))
   BASE=TVBASE*EXP(ETA(1))
   KTR1=THETA(2)
   GAM1=THETA(3)   
   KTR2=THETA(4) 
   GAM2=THETA(5)
   TVKCIRC=THETA(6)*EXP(AVAL*THETA(16))
   KCIRC=TVKCIRC*EXP(ETA(2))
   SHB=THETA(7)
   SLP=THETA(8)
   GAM=THETA(9)

   A_0(3)=(BASE*KTR2)/(KTR1)
   A_0(4)=(BASE*KTR2)/(KTR1)
   A_0(5)=(BASE*KTR2)/(KTR1)
   A_0(6)=(BASE*KTR2)/(KTR1)
   A_0(7)=BASE
   A_0(8)=BASE
   A_0(9)=BASE
   A_0(10)=BASE
   A_0(11)=(BASE*KTR2)/(KCIRC)
   A_0(12)=(BASE*KTR2)/(KCIRC)
   A_0(13)=(BASE*KTR2)/(KCIRC)
   A_0(14)=(BASE*KTR2)/(KCIRC)
   
$DES
   CE=(A(1)/V1)+0.0001
   EFF=SLP*CE**GAM
   DADT(1) = -K10*A(1) - K12*A(1) + K21*A(2)
   DADT(2) = K12*A(1) - K21*A(2)
   RET0=BASE*4
   RETT=(A(7)+A(8)+A(9)+A(10))
   RBC0=(BASE*KTR2/KCIR)*4
   RBCT=(A(11)+A(12)+A(13)+A(14))
   FBRET=(RET0/RETT)**GAM1
   FBRBC=(RBC0/RBCT)**GAM2
   DADT(3)=KTR1*(1-EFF)*A(3)*FBRET*FBRBC-KTR1*A(3)
   DADT(4)=KTR1*A(3)-KTR1*(1-EFF)*A(4)   
   DADT(5)=KTR1*(1-EFF)*A(4)-KTR1*(1-EFF)*A(5)
   DADT(6)=KTR1*(1-EFF)*A(5)-KTR1*(1-EFF)*A(6)
   DADT(7)=KTR1*(1-EFF)*A(6)-KTR2*A(7)
   DADT(8)=KTR2*A(7)-KTR2*A(8)
   DADT(9)=KTR2*A(8)-KTR2*A(9)
   DADT(10)=KTR2*A(9)-KTR2*A(10)
   DADT(11)=KTR2*A(10)-KCIR*A(11)
   DADT(12)=KCIR*A(11)-KCIR*A(12)
   DADT(13)=KCIR*A(12)-KCIR*A(13)
   DADT(14)=KCIR*A(13)-KCIR*A(14)
   DADT(15)=A(15)

$ERROR (OBSERVATION ONLY)
  ARC=A(7)+A(8)+A(9)+A(10)
  RBC=A(11)+A(12)+A(13)+A(14)
  IF(FLAG.EQ.5) IPRED = ARC
  IF(FLAG.EQ.6) IPRED = RBC
  IF(FLAG.EQ.7) IPRED = SHB*(ARC+RBC)
  IF(FLAG.EQ.5)  W     = SQRT((THETA(10)*IPRED)**2+THETA(11)**2)
  IF(FLAG.EQ.6)  W     = SQRT((THETA(12)*IPRED)**2+THETA(13)**2)
  IF(FLAG.EQ.7)  W     = SQRT(THETA(14)**2)
  IRES  = DV-IPRED
  IWRES = IRES/W
  Y     = IPRED+W*EPS(1)

;----PD-----
$THETA (0,20)         ;BASE
$THETA (0,0.04)       ;KTR1
$THETA (0,0.4)        ;GAM1
$THETA (0,0.034)      ;KTR2
$THETA (0,0.1)        ;GAM2
$THETA (0.00139 FIX)  ;KCIR
$THETA (0,0.02)       ;SHB
$THETA (0,0.001)      ;SLP
$THETA (0,1)          ;GAM

$THETA (0,0.1)        ;Prop_ARC
$THETA (0,11)         ;ADD_ARC
$THETA (0,0.1)        ;Prop_RBC
$THETA (0,130)        ;ADD_RBC
$THETA (0,5)          ;ADD_Hb

$THETA (-0.00297)     ;AGEE_BASE
$THETA (0.00743)      ;AGEE_KCIR
$THETA (-0.129)       ;GEN_BASE

$OMEGA BLOCK (2) 0.06 0.04 0.06   ;BASE_KCIR

$SIGMA 1.0 FIX

$EST MAXEVAL=9999 PRINT=5 METH=1 INTER SIGDIGITS=2 NOABORT
$COV UNCONDITIONAL MATRIX=S