;; 1. Based on: Run003_b
;; 2. Description: TOBRA HOUR 2C STR M3 op LOQ eta op CL en V1 COMB ERR MDRD LIN_SL CL + WT LIN on V1
;; x1. Author: user

$PROBLEM TOBRA 
$INPUT ID	TIME	AMT	RATE	DV	MDV	WT	MDRD	LLOQ


$DATA Simulated_data_tobramycin_obese.prn IGNORE=@
$SUBROUTINE ADVAN3 TRANS4
   ; One-compartment model with CL and V
   ; Do not use TAB when typing the model file!
$PK
    TVCL   = THETA(1)*(1+THETA(7)*(MDRD-115)); TVCL	


  TVV1    = THETA(2)*(WT/70); TVV1
  TVQ	=	THETA(3); TVQ
  TVV2	=	THETA(4); TVV2

;
CL = TVCL*EXP(ETA(1)) 
V1 = TVV1*EXP(ETA(2)) 
Q = TVQ*EXP(ETA(3))
V2 = TVV2*EXP(ETA(4))
 

  S1   = V1 ; conversion of amount in comp-1 to concentration
;
ET1=ETA(1)
ET2=ETA(2)
ET3=ETA(3)
ET4=ETA(4)


$THETA
(0, 6.32)  ; TVCL
(0, 10.6)  ; TVV1
(0, 6.69)  ; TVQ
(0, 4.34)  ; TVV2
(0, 0.116)  ; SD PROPORTIONAL ERR
(0, 0.346)  ; SD ADD
(0, 0.0099)  ;factor MDRD on CL

$OMEGA 
 0.0144   ; CL ETA 1
 0.06   ; V1 ETA 2
 0 FIX  ; Q ETA 3
 0 FIX  ; V2 ETA 4


$ERROR

IPRED  = F



PROP=THETA(5)*F ; proportional part 
ADD=THETA(6) ; additive part 
SD=SQRT(PROP*PROP + ADD*ADD) ; Standard deviation using proportional res error

IF(DV.GE.LLOQ)THEN ; LLOQ IS DEFINED IN DATASET
   F_FLAG=0
   Y=F+SD*ERR(1)   ; COMBINED ERROR MODEL
ELSE ; 
   F_FLAG=1
   Y=PHI((LLOQ-F)/SD)
ENDIF

IRES   = DV - IPRED
IWRES = IRES/SD

$SIGMA 
1 FIX     ; ERR 1 
;0.1      ; ERR 2



;$SIM (123456) ONLYSIM SUBPROBLEMS=1
$ESTIMATION METHOD=1 INTER MAXEVAL=0 POSTHOC LAPLACIAN; calculation method
$COVARIANCE PRINT=E; standard error of estimate is calculated


$TABLE ID	TIME	AMT	RATE	DV	MDV	EVID	WT	MDRD LLOQ NOPRINT ONEHEADER FILE=sdtab007_h_ddmore