;; PK-Pop model of sultiame with nonlinear distribution ;; Related article : Pharmacokinetic Profile of Sultiame in Healthy Volunteers with In Vitro Characterization of Its Uptake by Red Blood Cells ;; Kim Dao, Paul Thoueille, Laurent Arthur Decosterd, Thomas Mercier, Monia Guidi, Carine Bardinet, Sébastien Lebon, Eva Choong, ;; Arnaud Castang, Catherine Guittet, Luc-André Granier, Thierry Buclin ;; Under submission ;; Model author: Kim Dao ;; Date: 24.06.2019 ;; NCOMP=4 which are 1= absorption site, 2= plasma, 3= erythrocytes, 4= urines $PROBLEM PK $INPUT ID TTT DAT1=DROP TIME DV UVOL AMT MDV EVID CMT $DATA Simulated_data_PK_sultiame.csv IGNORE=I $SUBROUTINES ADVAN13 TOL=3 $MODEL NCOMP=4 $PK ; this is to calculate time after the dose IF (AMT.GT.0) THEN TDOS=TIME TAD=0.0 ENDIF IF (AMT.EQ.0) TAD=TIME-TDOS CL = THETA(1) * EXP(ETA(1)) ; clearance sultiame V2 = THETA(2) * EXP(ETA(2)) ; volume of distribution of plasma (L) V3 = THETA(3) ; volume of distribution of erythrocytes (L) KON = THETA(4) ; association constant in h^-1· mg^-1 BTOT = THETA(5) *EXP(ETA(4)) ; maximal binding capacity in mg KOFF = THETA(6) ; dissociation constant in h^-1 KA = THETA(7) ; absorption constant (h^-1) fixed to 1 KE = CL/V2 ; elimination constant QREN = THETA(8) * EXP(ETA(3)) ; renal extraction fraction S2 = V2 S3 = V3 S4 = UVOL/1000 ; conversion of units for volume of urines (L, in mL in dataset) ; differential equations according to model $DES DADT(1) = -KA * A(1) ; absorption compartment DADT(2) = KA * A(1) - KE * A(2) - KON * A(2) * (BTOT - A(3)) + KOFF * A(3) ; plasma compartment DADT(3) = KON * A(2) * (BTOT - A(3)) - KOFF * A(3) ; erythrocytes compartment DADT(4) = KE * A(2) * QREN ; urine compartment ; error models for plasma (Q2), erythrocytes (Q3) and urines (Q4) $ERROR Q2=0 Q3=0 Q4=0 IF(CMT==2) THEN Q2=1 IPRED2 = A(2)/S2 W2 = SQRT(THETA(9)**2*IPRED2**2 + THETA(10)**2) Y2 = IPRED2 + W2*EPS(1) IRES2 = DV-IPRED2 IWRES2 = IRES2/W2 ENDIF IF(CMT==3) THEN Q3=1 IPRED3 = A(3)/S3 W3 = SQRT(THETA(11)**2*IPRED3**2 + THETA(12)**2) Y3 = IPRED3 + W3*EPS(1) IRES3 = DV-IPRED3 IWRES3 = IRES3/W3 ENDIF IF(CMT.EQ.4.AND.EVID.EQ.0) THEN Q4=1 IPRED4 = A(4)/S4 W4 = SQRT(THETA(13)**2*IPRED4**2 + THETA(14)**2) Y4 = IPRED4 + W4*EPS(1) IRES4 = DV-IPRED4 IWRES4 = IRES4/W4 ENDIF IPRED=Q2*IPRED2+Q3*IPRED3+Q4*IPRED4 Y=Y2*Q2+Q3*Y3+Y4*Q4 IRES=Q2*IRES2+Q3*IRES3+Q4*IRES4 IWRES=Q2*IWRES2+Q3*IWRES3+Q4*IWRES4 $THETA (0, 7.4) ; Clearance (0, 0.7) ; V2 = Volume of distribution (plasma) (0, 3.1) ; V3 = Volume of distribution (erythrocytes) (0, 2) ; Kon = association constant (0, 140) ; Btot = total binding capacity of the receptor (0, 0.3) ; Koff = dissociation constant (1) FIX ; Ka = absorption constant (0, 0.5, 1) ; Qren = renal extraction ratio (0, 0.7) ; Prop.RE (sd) plasma (0) FIX ; Add.RE (sd) plasma (0, 0.22) ; Prop.RE (sd) erythrocytes (0, 0.0003) ; Add.RE (sd) erythrocytes (0, 0.1) ; Prop.RE (sd) urines (0) FIX ; Add.RE (sd) urines $OMEGA (0.1) ; IIV CL (0.1) ; IIV V2 (0.1) ; IIV QRen (0.1) ; IIV Btot $SIGMA 1 FIX ; Proportional error PK $EST METHOD=1 INTER MAXEVAL=9999 NOABORT SIGL=3 NSIG=1 PRINT=1 POSTHOC $COV $TABLE ID TIME DV CMT AMT MDV EVID NOPRINT NOHEADER FILE=tab0010 ; Xpose $TABLE ID TIME TAD AMT DV UVOL MDV CMT EVID IPRED IWRES CWRES ONEHEADER NOPRINT FILE=sdtab0010 $TABLE CL V2 V3 KA KE KON BTOT KOFF FIRSTONLY ONEHEADER NOPRINT FILE=patab0010