<p> 1Supplementary Material: NONMEM code </p><p>2$PROBLEM Dapagliflozin and D3OG FINAL model 3$INPUT ID TIME EVID AMT CMT DV UVOL BBWT AGE SEX BCRCLIBW CPCAT L2 4COMMENT=DROP 5$DATA data.csv IGNORE=@ 6 IGNORE=(L2.EQ.99) ; ignore repeated sampling rows 7 IGNORE=(TIME.GT.70.0) ; only first dose data 8$SUBROUTINE ADVAN13 TRANS1 TOL=9 9$MODEL 10 COMP=(DEPOT,DEFDOSE) ; 1_oral dose 11 COMP=(CENT) ; 2_parent central comp 12 COMP=(PPER) ; 3_parent peripheral comp 13 COMP=(MCEN) ; 4_metabolite central comp 14 COMP=(MPER) ; 5_metab peripheral comp (not used) 15 COMP=(PURN INITIALOFF) ; 6_parent urine 16 COMP=(MURN INITIALOFF) ; 7_metab urine 17 18$PK 19;---Covariate models from SCM 20 21;;; CLPGENDER-DEFINITION START 22IF(GENDER.EQ.1) CLPGENDER = 1 ; Most common 23IF(GENDER.EQ.0) CLPGENDER = (1 + THETA(28)) 24;;; CLPGENDER-DEFINITION END 25 26;;; CLP-RELATION START 27CLPCOV=CLPGENDER 28;;; CLP-RELATION END 29 30;;; CLMGENDER-DEFINITION START 31IF(GENDER.EQ.1) CLMGENDER = 1 ; Most common 32IF(GENDER.EQ.0) CLMGENDER = (1 + THETA(29)) 33;;; CLMGENDER-DEFINITION END 34 35;;; V3PCPCAT-DEFINITION START 36; Frequency of most common case is 52/64=0.8125 37;IF(CPCAT.EQ.0) V3PCPCAT_COMMON=1; Most common case, indicator variable is 1 38;IF(CPCAT.EQ.1) V3PCPCAT_COMMON=0 39V3PCPCAT = (1 + THETA(27)*(CPCAT)) 40;;; V3PCPCAT-DEFINITION END 41 42;;; V3P-RELATION START 43V3PCOV=V3PCPCAT 44;;; V3P-RELATION END 45 46;;; V2MCPCAT1-DEFINITION START 47; Frequency of most common case is 58/64=0.90625 48;IF(CPCAT1.EQ.0) V2MCPCAT1_COMMON=1; Most common case, indicator variable is 1 49;IF(CPCAT1.EQ.1) V2MCPCAT1_COMMON=0 50V2MCPCAT1 = (1 + THETA(26)*(CPCAT1)) 51;;; V2MCPCAT1-DEFINITION END 52 53;;; V2M-RELATION START 54V2MCOV=V2MCPCAT1 55;;; V2M-RELATION END 56 57;;; CLPOTHAGE-DEFINITION START 58CLPOTHAGE = ( 1 + THETA(25)*(AGE - 53.50)) 59;;; CLPOTHAGE-DEFINITION END 60 61;;; CLPOTH-RELATION START 62CLPOTHCOV=CLPOTHAGE*CLPCOV 63;;; CLPOTH-RELATION END 64 65;;; CLPM15CPCAT1-DEFINITION START 66; Frequency of most common case is 58/64=0.90625 67;IF(CPCAT1.EQ.0) CLPM15CPCAT1_COMMON=1; Most common case, indicator variable is 1 68;IF(CPCAT1.EQ.1) CLPM15CPCAT1_COMMON=0 69CLPM15CPCAT1 = (1 + THETA(24)*(CPCAT1)) 70;;; CLPM15CPCAT1-DEFINITION END 71 72;;; CLPM15BCRCLIBW-DEFINITION START 73CLPM15BCRCLIBW = ( 1 + THETA(23)*(BCRCLIBW - 80.14)) 74;;; CLPM15BCRCLIBW-DEFINITION END 75 76;;; CLPM15-RELATION START 77CLPM15COV=CLPM15BCRCLIBW*CLPM15CPCAT1*CLPCOV 78;;; CLPM15-RELATION END 79 80;;; CLMCPCAT-DEFINITION START 81; Frequency of most common case is 52/64=0.8125 82;IF(CPCAT.EQ.0) CLMCPCAT_COMMON=1; Most common case, indicator variable is 1 83;IF(CPCAT.EQ.1) CLMCPCAT_COMMON=0 84CLMCPCAT = (1 + THETA(22)*(CPCAT)) 85;;; CLMCPCAT-DEFINITION END 86 87;;; CLM-RELATION START 88CLMCOV=CLMCPCAT*CLMGENDER 89;;; CLM-RELATION END 90 91;---Setup for multidose transit compartment 92 IF (NEWIND.NE.2) THEN ; beginning of dataset, or new individual 93 TNXD = TIME ; TIME will be the time of the first record of that subject 94even if it's not a dose, but 95 PNXD = AMT ; the amount will be 0 if the first record is not a dose 96 ENDIF 97 TDOS = TNXD 98 PD = PNXD 99 IF(AMT.GT.0) THEN 100 TNXD=TIME 101 PNXD=AMT 102 ENDIF 103;---End 104 105;---Allometric scaling using baseline body weight (BBWT) 106 ASCL = (BBWT/70)**0.75 107 ASV = (BBWT/70)**1 108;---Dapagliflozin (parent[P]) 109 TVCLPM15 = THETA(1)*ASCL ; nonrenal CL to D3OG [M15] 110 TVCLPM15 = CLPM15COV*TVCLPM15 ; covariate models from SCM 111 112 TVCLPOTH = THETA(19)*ASCL ; nonrenal CL to other metabolites 113 TVCLPOTH = CLPOTHCOV*TVCLPOTH ; covariate models from SCM 114 115 TVCLPR = THETA(2)*BCRCLIBW ; renal CL scaled to baseline creatinine 116clearance 117 TVCLPR = CLPCOV*TVCLPR 118 119 TVV2P = THETA(3)*ASV ; cental volume of distribution 120 TVMTT = THETA(4) ; mean transit time 121 TVNN = THETA(5) ; number of transit compartments 122 TVQP = THETA(6)*ASCL ; inter-compartmental clearance 123 TVV3P = THETA(7)*ASV ; peripherval volume of distribution 124 TVV3P = V3PCOV*TVV3P ; covariate models from SCM 125;---Bioavailability (constrained between 0 and 1) 126 TVBIO = THETA(20) 127 PHI = LOG(TVBIO/(1-TVBIO)) 128 BIO = EXP(PHI+ETA(1))/(1+EXP(PHI+ETA(1))) 129;---D3OG (metabolite [M15]) 130 TVCLM = THETA(9)*BCRCLIBW ; renal CL scaled to baseline creatinine clearance 131 TVCLM = CLMCOV*TVCLM ; covariate models from SCM 132 TVV2M = THETA(10)*ASV ; central volume of distribution 133 TVV2M = V2MCOV*TVV2M ; covariate models from SCM 134;---MU 135 136 MU_2 = LOG(TVCLPR) 137 MU_3 = LOG(TVV2P) 138 MU_4 = LOG(TVQP) 139 MU_5 = LOG(TVV3P) 140 MU_6 = LOG(TVMTT) 141 MU_7 = LOG(TVNN) 142 MU_8 = LOG(TVCLM) 143 MU_9 = LOG(TVCLPOTH) 144 MU_10 = LOG(TVCLPM15) 145 MU_11 = LOG(TVV2M) 146;---Individual parameters 147 CLPR = EXP(MU_2 + ETA(2)) 148 V2P = EXP(MU_3 + ETA(3)) 149 QP = EXP(MU_4 + ETA(4)) 150 V3P = EXP(MU_5 + ETA(5)) 151 MTT = EXP(MU_6 + ETA(6)) 152 NN = EXP(MU_7 + ETA(7)) 153 CLM = EXP(MU_8 + ETA(8)) 154 CLPOTH = EXP(MU_9 + ETA(9)) 155 CLPM15 = EXP(MU_10 + ETA(10)) 156 V2M = EXP(MU_11 + ETA(11)) 157 158 CLPNR = CLPM15 + CLPOTH ; nonrenal clearance of dapagliflozin 159 CLP = CLPR + CLPNR ; total clearance of dapagliflozin 160 FM15 = CLPM15/CLP ; fraction metabolized to D3OG 161 FE = CLPR/CLP ; fraction of dapagliflozin excreted in urine 162 163;---Transit compartment 164 KTR =(NN+1)/MTT 165 F1 = 0 166 L = 0.9189385+(NN+.5)*LOG(NN)-NN+LOG(1+1/(12*NN)) ; logarithm of the approximation 167to the gamma function 168 LBPD = LOG(BIO*PNXD) 169 LKTR = LOG(KTR) 170 PFUNC = LBPD+LKTR-L 171;---Compartment scaling 172 S2 = V2P 173 S4 = V2M 174 UV = UVOL/1000 175 IF(UVOL.EQ.0.0) UV = 1 176 S6 = UV 177 S7 = UV 178;---Dapa disposition 179 K20 = CLPOTH/V2P ; nonrenal elmination to other metabolites 180 K26 = CLPR/V2P ; renal elimination 181 K24 = CLPM15/V2P ; nonrenal elimination to D3OG 182;---Dapa distribution 183 K23 = QP/V2P 184 K32 = QP/V3P 185;---M15 elimination 186 K47 = CLM/V2M ; assumed completely renal elimination 187;---end 188 189$DES 190 TEMPO = T-TDOS ; time after 191dose 192 IF(TEMPO.GT.0)THEN 193 KTT = KTR*TEMPO 194 DADT(1) = EXP(PFUNC+NN*LOG(KTT)-KTT)-KTR*A(1) ; 195dapagliflozin absorption 196 ELSE 197 DADT(1)=0 198 ENDIF 199 DADT(2) = KTR*A(1) - K26*A(2) - K23*A(2) + K32*A(3) -K24*A(2) - K20*A(2) ; 200dapagliflozin central compartment 201 DADT(3) = K23*A(2) - K32*A(3) ; 202dapagliflozin peropheral compartment 203 DADT(4) = K24*A(2) - K47*A(4) ; D3OG 204central compartmentt 205 DADT(5) = 0 ; not used 206 DADT(6) = K26*A(2) ; 207dapagliflozin urine 208 DADT(7) = K47*A(4) ; D3OG 209urine 210 211$ERROR 212 213 IPREDP = A(2)/V2P ; prediction dapagliflozin plasma 214 IPREDM = A(4)/V2M*585/409 ; prediction D3OG plasma 215 IPREDPU = A(6)/S6 ; prediction dapagliflozin urine 216 IPREDMU = A(7)/S7*585/409 ; prediction D3OG urine 217 218;---Parent plasma 219 PROPP = THETA(11)*IPREDP ; proportional component 220 ADDP = THETA(12) ; additive component 221 WP = SQRT(PROPP*PROPP + ADDP*ADDP) ; weighting 222;---Metabolite plasma 223 PROPM = THETA(13)*IPREDM 224 ADDM = THETA(14) 225 WM = SQRT(PROPM*PROPM + ADDM*ADDM) 226;---Parent urine 227 PROPPU = THETA(15)*IPREDPU 228 ADDPU = THETA(16) 229 WPU = SQRT(PROPPU*PROPPU + ADDPU*ADDPU) 230;---Metabolite urine 231 PROPMU = THETA(18)*IPREDMU + 1E-12 232 ADDMU = THETA(17) 233 WMU = SQRT(PROPMU*PROPMU + ADDMU*ADDMU) 234;---Replicate error 235 REPP = THETA(8) ; proportional replicate component plasma 236 REPU = THETA(21) ; proportional replicate component urine 237;---RUV models 238 IF (CMT.EQ.2) THEN 239 W = WP 240 IPRED = IPREDP 241 Y = IPREDP + WP*(EPS(1)*SQRT(1-REPP)+EPS(5)*SQRT(REPP)) 242 ENDIF 243 IF (CMT.EQ.4) THEN 244 W = WM 245 IPRED = IPREDM 246 Y = IPREDM + WM*(EPS(2)*SQRT(1-REPP)+EPS(5)*SQRT(REPP)) 247 ENDIF 248 IF (CMT.EQ.6) THEN 249 W = WPU 250 IPRED = IPREDPU 251 Y = IPREDPU + WPU*(EPS(3)*SQRT(1-REPU)+EPS(6)*SQRT(REPU)) 252 ENDIF 253 IF (CMT.EQ.7) THEN 254 W = WMU 255 IPRED = IPREDMU 256 Y = IPREDMU + WMU*(EPS(4)*SQRT(1-REPU)+EPS(6)*SQRT(REPU)) 257 ENDIF 258 IF (W.LT.1E-12) W = 1 259 IRES = DV - IPRED 260 IWRES = IRES/W 261 262 263$THETA ... 264$OMEGA ... 265$SIGMA 1.0 FIX ; plasma dapagliflozin 266$SIGMA 1.0 FIX ; plasma D3OG 267$SIGMA 1.0 FIX ; urine dapagliflozin 268$SIGMA 1.0 FIX ; urine D3OG 269$SIGMA 1.0 FIX ; plasma replicate 270$SIGMA 1.0 FIX ; urine plasma 271;---estimation methods 272$EST METHOD=1 INTER NOABORT MAXEVAL=9990 NSIG=3 SIGL=9 PRINT=2 MSFO=msf 273$EST METHOD=IMPMAP INTERACTION DF=1 EONLY=1 NITER=5 ISAMPLE=10000 274PRINT=1 275$COV UNCONDITIONAL 276 277;---table output 278$TABLE 279 280</p>