Dear NMusers group: I am puzzled by the result of a NONMEM analysis I am working on. I have modeled plasma conc versus effect data using ADVAN5 (simultaneous link, comp3=effect) and can get a reasonable fit for the PD but the PK IPRED versus observed plot has a very unusual S-shape. Fitting the same plasma conc independently using ADVAN3 with the same error structure does not produce such pattern. I log transform the plasma concentration data to obtain a better PK fit. Also I have built a non-linear binding equation into the error structure of the PKPD model. I have included the code below. Do you know what is wrong?
Many thanks in advance and I look forward to hear from you. Fatemeh Akhlaghi $PROBLEM ;MODEL DESC:PKPDLINKWITH BINDING PARAMETERS ;PROJECT NAME: EXAMPLE1 ;PROJECT ID: PKPDLINK MODEL ; MODEL: C = BIEXP; CE = C*KEO.EXP(-KEO.T); E = SIGM_EMX(CE) ; NOTE: MAY BE MORE ETAS HERE THAN REASONABLE ; NOTE: MODEL FOR C CAN BE MORE COMPLEX BY ADDING CMPTS ; ; THE DATA FILE CONTAINS BOTH CP AND EFFECT OBSERVATIONS. ; WHEN DV IS A CP OBSERVATION, CMT = 1 (OR 0), ; WHEN DV IS AN EFFECT OBSERVATION, CMT =2. $DATA ..\PKPDLINK1ADDDOSE.CSV IGNORE=C $INPUT ID OCC TIME AMT DV DV1 MDV CMT EVID WT TPRO ALB DOSE HT SEX AST TBIL UREA CREA WBC DROP=RBC $SUBROUTINES ADVAN=5 $MODEL COMP=(CENTRAL,DEFDOSE,DEFOBS) COMP=PERIPH COMP=EFFECT $PK K10=THETA(1) TVK12=THETA(2) K12=TVK12*EXP(ETA(1)) K13= .001*K10 ; TRIVIAL LOSS TO EFFECT COMPT K21=THETA(3) TVS1=THETA(4) S1=TVS1 ; V1 FOR DRUG K30=THETA(5) ; KEO E0=THETA(6)*EXP(ETA(2)) EMAX=THETA(7) C50=THETA(8)*EXP(ETA(3)) HILL=THETA(9) TVBMAX=THETA(10)*EXP(ETA(4)) BMAX=TVBMAX KD=THETA(11) KNS=THETA(12) W=THETA(13) S3=S1*K13/K30 ; PRESERVES CESS = CPSS $ERROR FLAG=0 IF(AMT.GT.0) FLAG=1 ;DOSING RECORD ONLY CP1=1 IF(F.NE.0) CP1=F LNCP=LOG(CP1+FLAG) ;TRANFORM THE PREDICTION TO THE LOG OF PRED Y1=LNCP+W*ERR(1) CP=0 IF(LNCP.GT.-4) CP=EXP(LNCP) CB=HT*((CP*BMAX/(CP+KD))+KNS*CP)+CP*(1-HT) E=E0*(1-(EMAX*(CB**HILL))/((C50**HILL)+(CB**HILL))) Y2=E+E*(ERR(2))+ERR(3) Q=1 IF(CMT.EQ.2) Q=0 ; CMT = 3 = EFFECT OBS Y=Q*Y1+(1-Q)*Y2 F1=Q*LNCP+(1-Q)*E IPRE=F1 DEL=0 IF(IPRE.EQ.0) DEL=1 W=IPRE+DEL IRES=IPRE-DV IWRES=IRES/W $THETA (0.01,0.5,1) ;K10 1 $THETA (0.1,1,2) ;K12 2 $THETA (0.01,0.05,0.5) ;K21 3 $THETA (0.1,4,10) ;V1 OR S1 4 $THETA (0.1,0.5,) ;K30 5 $THETA (0.1,0.2,) ;E0 6 $THETA (0.01,0.1,) ;EMAX 7 $THETA (0.1,150,) ;EC50 8 $THETA (2,4,6) ;HILL 9 $THETA (200,250,350) ;BMAX 10 $THETA (0.1,0.6,12) ;KD 11 $THETA (0.01,0.1,2) ;KNS 12 $THETA (0.001,0.1,) ;PRO RES ERR 13 $OMEGA BLOCK(3) 0.001 ;k12 0.0001 0.001 ;e0 0.0001 0.0001 0.01 ;ec50 $OMEGA 0.2 ;BMAX 4 $SIGMA 0.17 ;[A] SIGMA(1,1) 0.002 ;[A] SIGMA(2,2) 0.0001 ;[A] SIGMA(3,3) $COV PRINT=E $ESTIMATION METHOD=1 INTER PRINT=10 MAXEVAL=9999 SIGDIG=6 NOABORT Fatemeh Akhlaghi, PharmD, PhD Associate Professor in Pharmacokinetics Biomedical and Pharmaceutical Sciences (BPS) University of Rhode Island 125 Fogarty Hall, 41 Lower College Road Kingston, RI 02881, USA Phone/Fax: (401) 874 9205/(401) 874 2181 Email: [EMAIL PROTECTED] Laboratory Website: http://www.uri.edu/pharmacy/faculty/aps/akhlaghi/index
