$PROBLEM Population PK Analysis for Vismodegib

$INPUT C STUD PTNM ID TRT NDOS DOSE DADJ=DROP DSFQ=DROP NAMT=DROP AMT DUR=DROP
$INPUT RATE=DROP NTIM=DROP HOUR TFDS=DROP NDAY TIME=ADAY NGML=DROP UM=DROP
$INPUT LNNG=DROP DV=LNUM CMT EVID MDV=DROP BAAG AAGR AAG BALB ALBR ALBU FRMU PTS   
$INPUT BCC AGE BWTR=DROP BWT WTR=DROP WT=DROP HT=DROP RACE=DROP SEX BSA=DROP BMI 
$INPUT RTPR TPRO RWBC=DROP WBC=DROP RCRC=DROP CRCL RCRE=DROP CRET=DROP RSGO=DROP
$INPUT SGOT RSGP=DROP SGPT RTBI=DROP TBIL RTMB=DROP TMBD FLAG=DROP TYPE=DROP SS II 

;LNUM: dependent variable, ln(concentration) in uM
;PTS: 0=volunteer, 1=patient, 2=BCC
;BCC: 0=none, 1=LaBCC, 2=mBCC
;FRMU: 1=PhI tablet, 2=PhII tablet, 3=oral suspension
;SEX: 1=male, 2=female

$DATA pkall.new.no.outlier1.csv IGNORE=C
$SUBROUTINE ADVAN13 TOL=6
$MODEL 
   NCOMPARTMENTS=3
   COMP=(GUT)       ;CMT_1
   COMP=(TOTAL)     ;CMT_2
   COMP=(UNBOUND)   ;CMT_3

$PK
  ;molecular weight
   MW = 421.3

  ;new variables
   HV=0
   IF(PTS.EQ.0) HV=1
   FM=0
   IF(FRMU.EQ.1) FM=1

  ;covariates
   SAGE=THETA(9)*LOG(AGE/60)
   SWT=THETA(10)*LOG(BWT/75)

  ;unbound clearance (L/day) 
   CL=EXP(THETA(1)+SAGE+ETA(1))    

  ;central volume (L)      
   V=EXP(THETA(2)+SWT+ETA(2)) 

  ;dissociation constant (uM)           
   KD=EXP(THETA(3)+ETA(3))    

  ;Absorption rate constant (1/day)
   KA=EXP(THETA(4)+HV*THETA(5)+FM*THETA(8)+ETA(4))

  ;Bioavailability 
   F1=1
   IF(FRMU.EQ.1) F1=EXP(THETA(6)+HV*THETA(7))

$DES
  ;abs site (mg/day)
   DADT(1)= -KA*A(1)                             
   GI = A(1)

  ;umbound drug + drug-AAG (uM)
   CTOT=(A(2)*1000/MW)/V
   T1 = AAG - CTOT + KD
   U449 = (-T1 + SQRT(T1**2 + 4*CTOT*KD))/2     
   
  ;total drug (mg/day)
   DADT(2)= KA*A(1) - CL*U449*MW/1000   

$ERROR
   Q = 1
   IF (CMT.EQ.3) Q=0

  ;recalculate U449 in ERROR block
   CTOT0=(A(2)*1000/MW)/V
   T10 = AAG - CTOT0 + KD
   U4490 = (-T10 + SQRT(T10**2 + 4*CTOT0*KD))/2    

  ;total or unbound drug (uM)
   BLQ=(5.0*Q+0.1*(1-Q))/MW

   TY=Q*CTOT0+(1-Q)*U4490         
   IPRED=LOG(BLQ/2)
   IF(TY.GT.0) IPRED=LOG(TY)

   Y=IPRED+EPS(1)*Q+EPS(2)*(1-Q)

$THETA 
   (6,7.15,8)	      ;THETA1_LN(CL/F)_L/day
   (3.5,4.01,5)	      ;THETA2_LN(V/F)_L
   (-3.5,-2.88,-2)    ;THETA3_LN(KDAAG)_uM
   (1,1.98,3)         ;THETA4_LN(KA)
   (0,.469,1)         ;THETA5_population on Ka
   (-2,-1.13,0)       ;THETA6_LN(F1)
   (0,.574,1.5)       ;THETA7_population on F
   (-1,-.441,0)       ;THETA8_formulation on Ka
   (-1,-.35,1)        ;THETA9_age on CL
   (0,.5,1)           ;THETA10_weight on V

$OMEGA BLOCK(2) .255 .125 .259
$OMEGA .0423 0 FIXED
$SIGMA .0836 .183
$EST METHOD=1 POSTHOC MAX=9999 PRINT=5 NOABORT NSIG=2 SIGL=6
$COV MATRIX=R UNCONDITIONAL
$TABLE STUD ID TRT NDOS DOSE AAG AAGR ALBR ALBU TIME 
       NDAY HOUR GI TY AMT CMT IPRED CWRES 
       NOPRINT ONEHEADER FILE=sdtab120b
$TABLE STUD ID TRT NDOS DOSE AGE BMI BWT BAAG BALB SEX 
       CRCL SGOT SGPT TPRO TBIL BCC PTS FRMU TMBD
       CL V KA KD ETA(1) ETA(2) ETA(3) ETA(4)
       FIRSTONLY NOPRINT ONEHEADER FILE=patab120b