$PROBLEM New Bile release model $INPUT ID STUDY T2DM MEAL TIME DV VAR AMT KCAL RATE CMT MDV EVID PKFLG ID1 IT50 IKG0 ISLP IKDJ ISTEEP SET50 SEKG0 SESLP SEKDJ SESTEEP AGE WT $DATA Simulated_POOL_GB_4MEALS_run037.csv IGNORE=@ IGNORE=(MEAL.EQ.0) IGNORE=(MEAL.GT.6) IGNORE=(PKFLG.EQ.1) $ABBREVIATED DERIV2=NO $SUBROUTINE ADVAN13 TOL=6 $MODEL COMP=(DEPOT) ; 1. Calories in Stomach COMP=(TRANS) ; 2. Calories in intestine COMP=(SIGNAL) ; 3. Signal duodenum COMP=(GBVOL,DEFOBS) ; 4. Gallbladder volume $PK ;_________________________________ Covariates _________________________________; ; Baseline Covariates BASEWT = (1 + THETA(9)*(WT - 86)) ; Effect of WT BASECOV = BASEWT ; KR_B Covariates KR_BAGE = (1 + THETA(10)*(AGE - 64)) ; Effect of AGE KR_BCOV = KR_BAGE ; S50 Covariates S50AGE = (1 + THETA(11)*(AGE - 64)) ; Effect of AGE S50WT = (1 + THETA(12)*(WT - 86)) ; Effect of WT S50COV = S50AGE*S50WT ;______________________________ Gastric Emptying ______________________________; ; Fixed parameters (IPP) D1 = ID1 ; Meal infusion in study 3 ; Parameters with uncertainty (IPPSE) T50 = IT50*EXP(ETA(1)*SET50) ; Time to 50% onset STEEP = ISTEEP*EXP(ETA(2)*SESTEEP) ; Steepness of onset KG0 = IKG0*EXP(ETA(3)*SEKG0) ; Maximal rate of Gastric Emptying SLP = ISLP*EXP(ETA(4)*SESLP) ; Linear slope of glucose inhibition on KG KDJ = IKDJ*EXP(ETA(5)*SEKDJ) ; Signal attenuation ;_____________________________ Calories Parameters ____________________________; RAMAXD = 0.573*4.1 ; Maximum rate of absorption Kcal in intestine KM = 6.28*4.1 ; 50 % of absorption rate (kcal) F1 = 1 ; Trick to get dose of 0 IF(MEAL.EQ.0) F1 = 0 ;____________________________ Bile release Parameters _________________________; TVBASE = THETA(1)*BASECOV BASE = TVBASE*EXP(ETA(6)) ; Baseline volume of GB (mL) TVKR_B = (LOG(2)/THETA(2))*KR_BCOV KR_B = TVKR_B*EXP(ETA(7)) ; Rate constant of bile release (min-1) TVSMAX = THETA(3) SMAX = TVSMAX*EXP(ETA(8)) ; Max Calories effect on bile release TVS50 = THETA(8)*S50COV S50 = TVS50*EXP(ETA(9)) ; Signal that leads to 50% of max bile release rate RPRO = BASE*KR_B ; Rate of bile production mL/min A_0(4) = BASE ; Gallbladder baseline volume (mL) KDJ2 = (1/12) ; Rate cst of transfert from duod to jejunum (min-1) ;______________________________ Meals Composition _____________________________; IF(EVID.EQ.1.OR.EVID.EQ.4) TDOS = TIME ; Compile time after dose (TAD) GLUC = 0 ; Amount of carbohydrates (g) IF (MEAL==2) GLUC = 75 IF (MEAL==4) GLUC = 107 IF (MEAL==5) GLUC = 93 IF (MEAL==6) GLUC = 32 PROT = 0 ; Amount of proteins (g) IF (MEAL==4) PROT = 13 IF (MEAL==5) PROT = 11 IF (MEAL==6) PROT = 3 FAT = 0 ; Amount of fat (g) IF (MEAL==4) FAT = 2.5 IF (MEAL==5) FAT = 10 IF (MEAL==6) FAT = 40 ; Nutrient Potency TVPFAT = 1 TVPGLU = THETA(5) PFAT = TVPFAT ; Potency/g fat PPROT = THETA(4) ; Potency/g prot PGLU = TVPGLU ; Potency/g gluc ; Total meal nutrient effect on bile release EFAT = PFAT*FAT ; Total effect of fat in meal EPROT = PPROT*PROT ; Total effect of prot in meal EGLU = PGLU*GLUC ; Total effect of gluc in meal $DES ; Compartment Amounts X1 = A(1) ; Calories in Stomach (kcal) X2 = A(2) ; Calories in the Intestine (kcal) X3 = A(3) ; Calories in duodenum (kcal) X4 = A(4) ; Gallbladder volume (mL) IF(X2.LE.0) X2 = 1E-10 IF(X3.LE.0) X3 = 1E-10 X5 = 0 IF(KCAL>0) X5 = (X3/KCAL)*(EFAT + EPROT + EGLU) ; Effect of nutrients in upper GI on bile release ; Gastric delay TAD1 = T - TDOS ; Time after dose (TAD) LAG1 = 1 ; No onset water IF(STUDY.NE.3) THEN LAG1 = 1/(1+EXP(-STEEP*(TAD1-T50))) ; Onset Time stomach (min) ENDIF ;____________________________ Gastric Emptying Model __________________________; KG1 = KG0*(1+SLP*X2) ; Eq Diff RAD = RAMAXD*X2/(KM+X2) ; Rate of Absorption in intestine DADT(1) = -KG1*X1*LAG1 DADT(2) = KG1*X1*LAG1 -RAD -KDJ*X2 ; Calories in intestine (kcal) ;_____________________________ Bile release Model _____________________________; ; Differential Eq B_REL = 1+(SMAX*X5)/(S50+X5) RAD2 = RAMAXD*X3/(KM+X3) ; Rate of Absorption in intestine DADT(3) = KG1*X1*LAG1 -RAD2 -KDJ2*X3 DADT(4) = RPRO - X4*KR_B*B_REL ; Gallbladder volume (mL) $ERROR ; Compartment Amounts A1 = A(1) ; Calories in Stomach (kcal) A2 = A(2) ; Calories in the Intestine (kcal) A3 = A(3) ; Calories in duodenum (kcal) A4 = A(4) ; Gallbladder volume (mL) IF(A2.LE.0) A2 = 1E-10 IF(A3.LE.0) A3 = 1E-10 A5 = 0 IF(KCAL.GT.0) A5 = (A3/KCAL)*(EFAT + EPROT + EGLU) ; Effect of nutrients in upper GI on bile release ; Gastric delay TAD = TIME - TDOS ; Time after dose (TAD) LAG = 1 ; No onset water IF(STUDY.NE.3) THEN LAG = 1/(1+EXP(-STEEP*(TAD-T50))) ; Onset Time stomach (min) ENDIF ; Gallbladder volume fit IPRED = A4 IRES = DV - IPRED W=SQRT((THETA(6)*IPRED)**2 + THETA(7)**2) IWRES = IRES/W Y = IPRED+W*EPS(1) $THETA (0,35.8664) ; BASE $THETA (0,7.77817) ; HL KR_B $THETA (0,4.16398) ; SMAX $THETA (0,0.523112) ; PPROT $THETA (0,0.0114289) ; PGLUC $THETA (0,0.0726566) ; PROPERR $THETA (0,2.46054) ; ADDERR $THETA (0,2.76861) ; S50 $THETA 0.0121615 ; WT-BASE $THETA 0.0253338 ; AGE-KR_B $THETA 0.0284602 ; AGE-S50 $THETA -0.0163001 ; WT-S50 $OMEGA 1 FIX ; SE_T50 $OMEGA 1 FIX ; SE_STEEP $OMEGA 1 FIX ; SE_KG0 $OMEGA 1 FIX ; SE_SLP $OMEGA 1 FIX ; SE_KDJ $OMEGA 0.0740371 ; BASE $OMEGA 0.858318 ; KR_B $OMEGA 0 FIX ; SMAX $OMEGA 0.96543 ; S50 $SIGMA 1 FIX ; ERROR $ESTIMATION METHOD=1 SIGL=6 NSIG=2 INTER MAXEVAL=0 PRINT=1 NOABORT