;; 1. Based on: run126g ;; 2. Description: For DDMORE model repository ;; x1. Author: user $PROBLEM $INPUT ID TIME STUDY EVID CMT AMT RATE DV T2DM BASI INSU BW $DATA Simulated_ddmoremockdata2.txt IGNORE=@ $SUBROUTINE ADVAN13 TRANS1 TOL=6 $MODEL COMP=STOMACH ;1 Stomach compartment COMP=INTESTI ;2 Intestine compartment COMP=CENTP ;3 Central compartment COMP=PERIPHE ;4 Peripheral compartment COMP=SG ;5 Glucose stomach COMP=DG ;6 GLucose duodenum COMP=CENTG ;7 Central glucose COMP=PERIG ;8 Peripheral glucose COMP=EFF_G ;9 Effect compartment COMP=EFF_I ;10 Effect compartment COMP=JEJUN ;11 Jejunum compartment COMP=ILEUM ;12 Ileum compartment COMP=KUML ;13 Cumulative first pass loss paracetamol COMP=GLP1 ;14 GLP1 COMP=GIP ;15 GIP $PK ;---- Paracetamol parameters --- CL = THETA(1)*EXP(ETA(1)) ; Paracetamol clearance V1 = THETA(2)*EXP(ETA(2)) ; Central volume of distribution Q2 = THETA(3) ; Intercompartmental clearance V2 = THETA(4) ; Peripheral volume of distribution KA = THETA(5) ; Absorption rate constant IF(STUDY.EQ.1) APAPBL = THETA(6)*EXP(ETA(3)) ; Baseline noise IF(STUDY.EQ.2) APAPBL = THETA(6)*EXP(ETA(4)) ; Baseline noise IF(STUDY.EQ.3) APAPBL = THETA(6)*EXP(ETA(5)) ; Baseline noise K12A = Q2/V1 K21A = Q2/V2 KE = CL/V1 ;---- Glucose parameters ------- GSSH = THETA(7)*EXP(ETA(6)) ; Glucose baseline healthy GSSD = THETA(8)*EXP(ETA(7)) ; Glucose baseline T2DM VG = THETA(9)*BW/70 ;Central volume for glucose CLGH = THETA(10)*EXP(ETA(8)) ;Glucose clearance CLGIH = THETA(11)*EXP(ETA(9)) ;Insulin dependant glucose clearance Q = THETA(12) ;Intercompartment glucose clearance VP = THETA(13) ;Periferal volume for glucose KGE1 = THETA(14) KIE = THETA(15) CLGD = THETA(16)*EXP(ETA(10)) CLGID = THETA(17)*EXP(ETA(11)) FPGH = THETA(18) FPGD = THETA(19) RAMAXD = THETA(20) ; Maximum rate of absorption glucose RAMAXJ = THETA(21) RAMAXI = THETA(22) KMG = THETA(23) ; 50 % of absorption rate ;------------------------------- IF(T2DM.EQ.0) GSS = GSSH ; Healthy have healthy glucose baseline IF(T2DM.EQ.1) GSS = GSSD ; T2DM have T2DM glucose baseline IF(T2DM.EQ.0) CLG = CLGH ; Healthy IF(T2DM.EQ.1) CLG = CLGD ; T2DM IF(T2DM.EQ.0) CLGI = CLGIH ; Healthy IF(T2DM.EQ.1) CLGI = CLGID ; T2DM IF(T2DM.EQ.0) GPRG = -2.79 ; Healthy IF(T2DM.EQ.1) GPRG = 0 ; T2DM IF(T2DM.EQ.0) FPG = FPGH ; Healthy IF(T2DM.EQ.1) FPG = FPGD ; T2DM ISS = BASI/6.945 ; Obeserved baseline in mU/L K12G = Q/VG K21G = Q/VP KG = CLG/VG KGI = CLGI/VG GPRO = GSS*(KG+KGI*ISS)*VG*180/1000 ;Baseline glucose production in amount mMol => g, since dose is in g ;---- Gastric emptying --------------- KW = THETA(24)*EXP(ETA(12)) ; "Water" emptying GLUMAX = THETA(25) ; Maximum inhibition of glucose dose IGD50 = THETA(26)*EXP(ETA(13)) ; 50% of glucose inhibition GAM = THETA(27) IF(STUDY.EQ.1) T50 = THETA(28)*EXP(ETA(14)) IF(STUDY.EQ.2) T50 = THETA(28)*EXP(ETA(15)) IF(STUDY.EQ.3) T50 = THETA(28)*EXP(ETA(16)) ;----- Saturable first pass effect --- VMAX = THETA(29) KMAC = THETA(30) ;----- Incretin parameters ----------- EMGLP1D = THETA(31) EMGLP1I = THETA(32) E50GLP1I = THETA(33) EMGIP = THETA(34) E50GIP = THETA(35) BGLP1 = THETA(36)*EXP(ETA(17)) BGIP = THETA(37)*EXP(ETA(18)) KEGIP = LOG(2)/7 KEGLP1 = LOG(2)/1.5 ;----- GI parameters ----------------- TT = 240 ; min transit time through small intestine FLD = 0.08 ; Fractional length duodenum FLJ = 0.37 ; Fractional length jejunum FLI = 0.55 ; Fractional length ileum DTT = TT*FLD ; Duodenum transit time KDJ = 1/DTT ; K duodenum jejunum JTT = TT*FLJ ; Jejunum transit time KJI = 1/JTT ; K jejunum ileum ITT = TT*FLI ; Ileum transit time KIC = 1/ITT ; K ileum colon ;----------------------------------------------------- A_0(1) = 0 ; Stomach paracetamol A_0(2) = 0 ; Duodenum paracetamol A_0(3) = 0 ; Central paracetamol A_0(4) = 0 ; Peripheral paracetamol A_0(5) = 0 ; Stomach glucose A_0(6) = 0 ; Duodenum glucose A_0(7) = GSS*VG*180/1000 ; Central glucose A_0(8) = K12G/K21G*GSS*VG*180/1000 ; Peripheral glucose A_0(9) = GSS ; Glucose on glucose production A_0(10)= ISS ; Insulin on glucose elimination A_0(11) = 0 ; Jejunum glucose A_0(12) = 0 ; Ileum glucose A_0(13) = 0 ; CFPL A_0(14) = BGLP1 A_0(15) = BGIP $DES GLURAT = A(9)/GSS GGPR = (GLURAT+0.0001)**GPRG ; Glucose on glucose production GPRT = GPRO*GGPR ; Glucose production a.k.a GPRD RAD = RAMAXD*A(6)/(KMG+A(6)) RAJ = RAMAXJ*A(11)/(KMG+A(11)) RAI = RAMAXI*A(12)/(KMG+A(12)) RA = RAD + RAJ + RAI DUOGLU = A(6) IF(DUOGLU.LT.0) DUOGLU = 0 GLUINHI = GLUMAX*(DUOGLU+0.00001)**GAM/(IGD50**GAM+(DUOGLU+0.00001)**GAM) KS = KW*(1-GLUINHI) IF(KS.LT.0) KS = 0 LAG = 1/(1+EXP(-10*(T-T50))) FPL = VMAX*A(2)/(KMAC+A(2)) DADT(1) = -KS*A(1)*LAG ;1 Stomach DADT(2) = KS*A(1)*LAG -KA*A(2)-FPL ;2 Intestine DADT(3) = KA*A(2)- (KE+K12A)*A(3) + K21A*A(4);3 Central DADT(4) = K12A*A(3) - K21A*A(4) ;4 Peripheral DADT(5) = -KS*A(5)*LAG ;5 Stomach compartment (g) DADT(6) = KS*A(5)*LAG -RAD -KDJ*A(6) ;6 Duodenum compartment (g) DADT(7) = RA*FPG + GPRT +K21G*A(8) -(K12G+KG)*A(7)- KGI*A(7)*A(10) ;7 Central glucose, amount (g) DADT(8) = K12G*A(7) -K21G*A(8) ;8 Periferal glucose (g) DADT(9) = KGE1*(A(7)/VG/180*1000 - A(9)) ;9 Effect compartment, Glucose on glucose production g => mM DADT(10) = KIE*(INSU/6.945 - A(10)) ;10 Effect compartment, Insulin on glucose elimination, pM => µU/ml DADT(11) = KDJ*A(6) -KJI*A(11) - RAJ ;11 Jejunum DADT(12) = KJI*A(11) - RAI ;12 Ileum DADT(13) = FPL ;13 Cumulative amount lost ;----- GIP & GLP1 ------------------------------ DADT(14) = -KEGLP1*(A(14)-BGLP1)+ BGLP1*KEGLP1*(EMGLP1D*A(6)+EMGLP1I*A(12)/(E50GLP1I+A(12))) ; 14 GLP1 DADT(15) = -KEGIP *(A(15)-BGIP )+ BGIP *KEGIP * EMGIP*A(6)/(A(6)+E50GIP) ; 15 GIP ;----------------------------------------------------------- $ERROR STOM = A(1) INTE = A(2) CAC = A(3)/151.17/V1*1000 ; Convert amount (mg) to concentration (µM) PAC = A(4) STOMG = A(5) DUODG = A(6) CGLU = A(7)*1000/(180*VG) ; convert g to mM CPER = A(8)*1000/(180*VP) ; convert g to mM GGP = A(9) IGE = A(10) JEJUG = A(11) ILEUG = A(12) CFPL = A(13) CGLP1 = A(14) CGIP = A(15) IF(CMT.EQ.3) IPRED = LOG(CAC+APAPBL+0.00001) IF(CMT.EQ.3) W = SQRT(SIGMA(1)) IF(CMT.EQ.3) Y = IPRED + EPS(1) IF(CMT.EQ.7) IPRED = LOG(CGLU+0.00001) IF(CMT.EQ.7) W = SQRT(SIGMA(2)) IF(CMT.EQ.7) Y = IPRED + EPS(2) IF(CMT.EQ.14) IPRED = LOG(CGLP1+0.00001) IF(CMT.EQ.14) W = SQRT(SIGMA(3)) IF(CMT.EQ.14) Y = IPRED + EPS(3) IF(CMT.EQ.15) IPRED = LOG(CGIP+0.00001) IF(CMT.EQ.15) W = SQRT(SIGMA(4)) IF(CMT.EQ.15) Y = IPRED + EPS(4) IRES = DV-IPRED IF(W.EQ.0) W = 1 IWRES = IRES/W ;--- Initial estimates --- $THETA (0, 0.344) ; 1 CL (L/min) (0, 27) ; 2 V1 (L) (0, 0.675) ; 3 CLQ(L/min) (0, 22) ; 4 V2 (L) (0.14) FIX ; 5 KA (/min) 5 min (0, 6.54) ; 6 APAPBL (µM) (0, 5.27) ; 7 GSSH (mM) (0, 7.48) ; 8 GSSD (mM) (9.33) FIX ; 9 VG (L) (0.0894) FIX ; 10 CLGH (L/min) (0, 0.00663,0.0083) ; 11 CLGIH (L/min/(µU/mL) (0.442) FIX ; 12 Q (L/min) (8.56) FIX ; 13 VP (L) (0.0573) FIX ; 14 KGE1 (0.0213) FIX ; 15 KIE (0.0287) FIX ; 16 CLGD (L/min) (0, 0.00547,0.0083) ; 17 CLGID (L/min/(µU/mL) (0, 0.909,1) ; 18 FPGH (1) FIX ; 19 FPGD (0, 0.576) ; 20 RAMAXD rate (0, 2.06) ; 21 RAMAXJ rate (0, 1.33) ; 22 RAMAXI rate (0, 6.32) ; 23 KMG (g) (0.14) FIX ; 24 KW (/min) (1) FIX ; 25 GLUMAX (0, 7.42) ; 26 IGD50 (0, 14) ; 27 GAM (15, 20,30) ; 28 T50 (0, 17) ; 29 VMAX (0, 168) ; 30 KMAC (0, 0.0279,300) ; 31 EMGLP1D (0, 1.98,300) ; 32 EMGLP1I (0, 0.0525) ; 33 E50GLPI (0, 14.3,300) ; 34 EMGIP (0, 2.57,300) ; 35 E50GIP (0, 17.1) ; 36 BGLP1 (0, 8.03) ; 37 BGIP $OMEGA 0.109 ; 1 IIV CL $OMEGA 0.143 ; 2 IIV V1 $OMEGA BLOCK(1) 0.0338 ; 3 APAPBL $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME ;Glucose $OMEGA 0.00177 ; 6 GSSH $OMEGA 0.00762 ; 7 GSSD $OMEGA 0.348 FIX ; 8 CLGH $OMEGA 0.226 ; 9 CLGIH $OMEGA 0.348 FIX ; 10 CLGD $OMEGA 0.209 ; 11 CLGID ;Gastric emptying $OMEGA 0.25 FIX ; 12 KW $OMEGA 0.114 ; 13 IGD50 $OMEGA BLOCK(1) 0.0538 ; 14 LAG $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME ;Incretins $OMEGA 0.0649 ; 17 BGLP1 $OMEGA 0.177 ; 18 BGIP $SIGMA 0.0185 ; Paracetamol $SIGMA 0.0123 ; Glucose $SIGMA 0.129 ; GLP-1 $SIGMA 0.314 ; GIP $ESTIMATION METHOD=0 SIGL=6 NSIG=2 INTER MAXEVAL=9999 PRINT=1 NOABORT ;$ESTIMATION METHOD=IMP EONLY=1 ISAMPLE=1000 NITER=5 ;$COVARIANCE UNCONDITIONAL MATRIX=R ;$SIM (43658) NSUB=1 ;$TABLE ID TIME STUDY EVID CMT AMT RATE INSU BASI BW DV T2DM NOPRINT NOAPPEND ONEHEAD FILE=simdata126h