$PROB RUN#
$INPUT C ID STUDY COHT ROUTE AMT TIME BLQ DV EVID MDV CMT 
 IADA ITA1 ITA2 ITA3 ITA4 ITA5 RACE WT BABSEOS

$DATA metapd.csv IGNORE=C
$SUBROUTINE ADVAN13 TRANS1 TOL=9
$MODEL
 COMP=(SC) COMP=(CENTRAL) COMP=(PERIPH) 
 COMP=(EOS1) COMP=(EOS2) COMP=(EOS3) COMP=(EOS4) COMP=(EOS5) COMP=(EOS DEFOBS) 
 
$PK
   RACEJ=0 
 	IF (RACE.EQ.2) RACEJ=1
   CL = THETA(1)*(WT/71.67)**THETA(7)*EXP(ITA1)*EXP(IADA*THETA(10))
   VC = THETA(2)*(WT/71.67)**THETA(8)*EXP(ITA2)
   VC=VC*(1-RACEJ)+VC*THETA(11)*RACEJ
   Q = THETA(3)
   VP = THETA(4)*(WT/71.67)**THETA(9)*DEXP(ITA3)
   KA=THETA(5)*DEXP(ITA4)
   F1=THETA(6)*DEXP(ITA5)
   K20=CL/VC
   K23=Q/VC
   K32=Q/VP

;PD
   EMAX=THETA(12)*DEXP(ETA(1))
   EC50=THETA(13)*DEXP(ETA(2))
   LSPN=THETA(14)*DEXP(ETA(3))
   W = EXP(THETA(15)) 
   EOS0=BABSEOS*1000*EXP(ETA(4)*W) 
   S0=EOS0/LSPN
;
   A_0(4)=S0*LSPN/5
   A_0(5)=S0*LSPN/5
   A_0(6)=S0*LSPN/5
   A_0(7)=S0*LSPN/5
   A_0(8)=S0*LSPN/5
   A_0(9)=S0*LSPN  

$DES
  C2=A(2)/VC
  KBMT=5/LSPN
  K563=EMAX*C2/(EC50+C2)
  EOS=A(4)+A(5)+A(6)+A(7)+A(8)
;PK
  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)
;BLOOD EOS
  DADT(4)=S0-KBMT*A(4)-K563*A(4)
  DADT(5)=KBMT*A(4)-KBMT*A(5)-K563*A(5)
  DADT(6)=KBMT*A(5)-KBMT*A(6)-K563*A(6)
  DADT(7)=KBMT*A(6)-KBMT*A(7)-K563*A(7)
  DADT(8)=KBMT*A(7)-KBMT*A(8)-K563*A(8)
  DADT(9)=S0-KBMT*A(8)-K563*EOS

$ERROR(OBSERVATIONS ONLY)

 IPRED=LOG(F) 
 IEOS=F
 IRES = DV-IPRED 
 IWRES=IRES/W
 LOQ=LOG(10)
 ABLQ=(LOQ-IPRED)/W
  IF(ABLQ.LT.(-2)) ABLQ=-2
 CUMD=PHI(ABLQ)
 
	IF (BLQ.EQ.0) THEN 
		F_FLAG=0 
		Y = IPRED+ERR(1)*W
	ENDIF
 
	IF (BLQ.EQ.1) THEN 
		F_FLAG=1 
		Y=CUMD 
	ENDIF 

$THETA 
 0.323 	FIX          	;1 CL (L/d)
 3.16 	FIX          	;2 V2 (L)
 0.939 	FIX          	;3 Q (L)
 2.83 	FIX          	;4 V3 (L/d)
 0.252 	FIX          	;5 KA (day-1)
 0.526 	FIX          	;6 F1 
 0.75 	FIX          	;7 CL ~ WT
 0.651 	FIX			;8 V2 ~ WT
 0.576 	FIX          	;9 V3 ~ WT
 1.52 	FIX	    		;10 CL ~ ADA
 1.34 	FIX 	    		;11 VC~RACEJ (Japanese HV)	
 25					;12 [Emax, d-1]
 (0,0.1) 				;13 [EC50, ug/mL]
 2.64 FIX				;14 [Lifespan, d]
 -0.4					;15 proportional error (exponent)

$OMEGA
 0.2 ;[P] INTERIND VAR IN EMAX
 0.2 ;[P] INTERIND VAR IN EC50
 0.2 ;[P] INTERIND VAR IN LSPN
 1 FIX

$SIGMA 1 FIX 

$EST METHOD=1 INTERACTION LAPLACIAN NUMERICAL SLOW MAXEVAL=99999 NOABORT PRINT=5 SIGL=6  NSIG=3 MSFO=metapd019a.MSF
$TABLE ID STUDY ROUTE COHT TIME IEOS CMT BLQ EVID IPRED IWRES EMAX EC50 LSPN ETA1 ETA2 ETA3 IADA RACE WT BABSEOS NOPRINT ONEHEADER FILE=metapd019a.tab