$PROBLEM    Multiple-dose model, reduced full covariate
$INPUT      C ID STDY TNOM TIME TADA AMT RATE DV EVID MDV 
            CMT TTYPE DOSE AGE WT_BL SEX RACE AST ALB EGFR
            PLAT CRP TS_BL HAHAEVER CMOPI PMBIO 
$DATA      avelumab_data.csv
           IGNORE=C 
$SUBROUTINE ADVAN3 TRANS4
$PK      

WTT = WT_BL
IF(WT_BL.LE.0) WTT = 71

ALBT = ALB
IF(ALB.LE.0)  ALBT = 39
IF(ALB.GT.61) ALBT = 61 

EGFRT = EGFR
IF(EGFR.LE.0)   EGFRT = 85.9
IF(EGFR.GT.226) EGFRT = 226 

TST = TS_BL
IF(TS_BL.LE.0)   TST = 60
IF(TS_BL.GT.388) TST = 388 

CRPT = CRP
IF(CRP.LE.0)   CRPT = 10.7
IF(CRP.GT.250) CRPT = 250 

PLATT = PLAT
IF(PLAT.LE.0)   PLATT = 247
IF(PLAT.GT.600) PLATT = 600 

ASTT = AST
IF(AST.LE.0)   ASTT = 22
IF(AST.GT.105) ASTT = 105


; CL ############################

CLWT    = (WTT/71)**THETA(10)
CLSEX   = 1
IF(SEX.EQ.1) CLSEX = 1 + THETA(11)
CLAGE   = (AGE/63)**THETA(12)
CLRACE  = 1
IF(RACE.EQ.2) CLRACE = 1 + THETA(13)
CLALB   = (ALBT/39)**THETA(14)
CLEGFR  = (EGFRT/85.9)**THETA(15)
CLTS    = (TST/60)**THETA(16)
CLHAHA  = 1
IF(HAHAEVER.EQ.1) CLHAHA = 1 + THETA(17)
CLCRP   = (CRPT/10.7)**THETA(18)
CLPLAT  = (PLATT/247)**THETA(19)
CLAST   = (ASTT/22)**THETA(20)
CLCMOPI = 1
IF(CMOPI.EQ.0) CLCMOPI = 1 + THETA(21)
CLPMBIO = 1
IF(PMBIO.EQ.1) CLPMBIO = 1 + THETA(22)

CLCOV1 = CLWT * CLSEX * CLAGE * CLRACE * CLALB * CLEGFR * CLTS  
CLCOV2 = CLHAHA * CLCRP * CLPLAT * CLAST * CLCMOPI * CLPMBIO 
CLCOV = CLCOV1 * CLCOV2

; V1 ############################

V1WT    = (WTT/71)**THETA(23)
V1SEX   = 1
IF(SEX.EQ.1) V1SEX = 1 + THETA(24)
V1ALB   = (ALBT/39)**THETA(25)
V1PMBIO = 1
IF(PMBIO.EQ.1) V1PMBIO = 1 + THETA(26)

V1COV = V1WT * V1SEX * V1ALB * V1PMBIO

TVCL   = THETA(1)*CLCOV
TVV1   = THETA(2)*V1COV
TVV2   = THETA(3)
TVQ    = THETA(4)

TIMEDAY = TIME / 24

TVTMAX = THETA(5) 
TVT50  = THETA(6)
TVGAM  = THETA(7)
IF(TTYPE.EQ.6) THEN
  TVTMAX = THETA(27)
  TVGAM  = THETA(28)
ENDIF
IF(TTYPE.EQ.14) THEN
  TVTMAX = THETA(29)
  TVT50  = THETA(30)
  TVGAM  = THETA(31)
ENDIF

TMAX = TVTMAX + ETA(4)
T50  = TVT50
GAM  = TVGAM

CL     = TVCL*EXP(TMAX*TIMEDAY**GAM/(T50**GAM + TIMEDAY**GAM))*EXP(ETA(1))
V1     = TVV1*EXP(ETA(2))
V2     = TVV2*EXP(ETA(3))
Q      = TVQ

S1=V1
S2=V2

$ERROR        

IPRED         = F
IRES          = DV-IPRED
W = SQRT((THETA(8)*THETA(8)*F*F)+THETA(9)*THETA(9))
IF (W.EQ.0) W = 1
IWRES         = IRES/W
Y = IPRED+W*ERR(1); add prop res error


$THETA  (0,0.0308287) ; 1 CLL - Clearance linear [L/h]
 (0,3.42088) ; 2 V1 - central volume of distribution [L]
 (0,0.920861) ; 3 V2 - peripheral volume of distribution [L]
 (0,0.0313042) ; 4 Q - intercompartmenal clearance [L/h]
 0 FIX ; 5 TMAX
 (0,68.6323) ; 6 T50
 (0,2.87983,5) ; 7 GAM
 (0,0.162285) ; 8 Prop residual error
 (0,2.43039) ; 9 Add residual error
 (-5,0.322995,5) ; 10 WT on CL
 (-1,-0.150614,5) ; 11 SEX (f) on CL
 (-5,-0.11965,5) ; 12 AGE on CL
 (-1,-0.120586,5) ; 13 RACE (b) on CL
 (-5,-0.43756,5) ; 14 ALB on CL
 (-5,0.0586609,5) ; 15 EGFR on CL
 (-5,0.0592001,5) ; 16 TS on CL
 (-1,0.123127,5) ; 17 HAHA (ever) on CL
 (-5,0.0677849,5) ; 18 CRP on CL
 (-5,0.06053,5) ; 19 PLAT on CL
 (-5,-0.0513872,5) ; 20 AST on CL
 (-1,-0.0448178,5) ; 21 CMOPI (0) on CL
 (-1,-0.0501005,5) ; 22 PMBIO (1) on CL
 (-5,0.361469,5) ; 23 WT on V1
 (-1,-0.159749,5) ; 24 SEX (m) on V1
 (-5,-0.277466,5) ; 25 ALB on V1
 (-1,-0.0525806,5) ; 26 PMBIO (1) on V1
 -0.265677 ; 27 TMAX head and neck
 (0,0.95972) ; 28 GAM head and neck
 -0.388541 ; 29 TMAX MCC
 (0,131.417) ; 30 T50 MCC
 (0,1.67434) ; 31 GAM MCC
$OMEGA  BLOCK(3)
 0.0536088  ;   1 OM CLL
 0.0172087 0.0331655  ;    2 OM V1
 0.0625345 -0.0140066 0.853445  ;    3 OM V2
$OMEGA  0.0609668  ; 4. IIV on TMAX
$SIGMA  1  FIX  ;  SIs as TH

$ESTIMATION NOABORT SIGDIG=3 MAXEVAL=9999 PRINT=5 METHOD=1 INTERACTION
$COVARIANCE PRINT=E UNCONDITIONAL MATRIX=S