$PROB RUN#
$INPUT C STUDY ID AGE SEX RACE COHT ROUTE WT ADA DV 
       AMT TIME TSLD EVID MDV CMT
$DATA pk2.csv IGNORE=C
$SUBROUTINE ADVAN8 TRANS1 TOL=6
$MODEL
 COMP=(SC) COMP=(CENTRAL) COMP=(PERIPH) 

$PK
  IADA=0 
  	IF (ADA.GE.400) IADA=1

  RACEJ=0 
 	IF (RACE.EQ.2) RACEJ=1

  CL = THETA(1)*(WT/71.67)**THETA(7)*EXP(ETA(1))*EXP(IADA*THETA(10))
  VC = THETA(2)*(WT/71.67)**THETA(8)*EXP(ETA(2))
  VC=VC*(1-RACEJ)+VC*THETA(11)*RACEJ
  Q = THETA(3)
  VP = THETA(4)*(WT/71.67)**THETA(9)*DEXP(ETA(3))
  KA=THETA(5)*DEXP(ETA(4))
  F1=THETA(6)*DEXP(ETA(5))
  S2 = VC/1000
  K20=CL/VC
  K23=Q/VC
  K32=Q/VP

$DES
  DADT(1)=-KA*A(1)
  DADT(2)=KA*A(1)-K20*A(2)-K23*A(2)+K32*A(3)
  DADT(3)=K23*A(2)-K32*A(3)

$ERROR
  IPRED=F
  W=IPRED+0.00001
  IRES=DV-IPRED
  IWRES=IRES/W
  SC=0 
	IF(ROUTE.EQ.2) SC=1
  	YSC=F*(1+ERR(1))+ERR(2)
	YIV=F*(1+ERR(3))+ERR(4)
  Y=YSC*SC+YIV*(1-SC)

$THETA 
 (0, 0.3)          ;1 	CL (L/d)
 (0, 3.5)          ;2 	V2 (L)
 (0, 0.7)          ;3	Q (L)
 (0, 2.5)          ;4	V3 (L/d)
 (0, 0.23)         ;5	KA (day-1)
 (0, 0.5, 1)       ;6	F1 
  0.75 FIX         ;7	CL ~ WT
 (0, 0.9)          ;8	V2 ~ WT
 (0, 0.9)          ;9	V3 ~ WT
  0.1	          	  ;10	CL ~ ADA
 (0,1)		  ;11	VC~RACEJ (Japanese HV)	

$OMEGA  
0.09                       
0.08                             
0.1
0.2
0.2

$SIGMA 
0.1             	;Proportional Error SC
100			;Additive Error SC
0.1			;Proportional Error IV
10			;Additive Error IV

$EST METHOD=1 INTER MAXEVAL=9999 PRINT=5 NOABORT NSIG=3
;$COV 
$TABLE ID STUDY TIME TSLD CMT EVID IPRED IWRES CWRES CL VC Q VP F1 KA ETA1 ETA2 ETA3 ETA4 ETA5 RACE WT ADA IADA NOPRINT ONEHEADER FILE=metapk_final.tab