KPD Model

Hi I have collected data on absolute neutrophil counts (ANC) from children (n=30) with acute leukaemia (from the maintenance phase of therapy, lasting up to 3 years). I also have the 6-Mercaptopurine dosing data, but no plasma concentration data. Each child attended clinic every 2 weeks to measure ANC and adjustment of 6-MP dose. All children received 75mg/m2. Doses started at 100%, but were reduced to 75% or 50% depending on ANC count. On most occasions when the ANC level dropped below 1.0, the 6-MP was withheld until the ANC level returned back to >1. I have tried to implement a K-PD model as described by P. Jacqmin et al (JPP;34(1) 2007) without success. I provide the code and snippet of the data file (The dose is actual dose administered and I have initiated the PD CMP=3 by putting the initial amount in the AMT column). I have not had any success with trying to develop a base model; the model spectactularly fails to describe the observed data. The population PRED estimate is virtually the same (a constant) for all time points for all patients (even though ANC sampling times and doses varied between patients). The IPRED is also the same as PRED. I have tried many different initial estimates. What am I doing wrong? Can anyone please diagnose the problem? $MODEL NPAR=6 NCOMP=3 COMP=(DOSE) COMP=(BIOPHASE) COMP=(ANCLEVEL) $PK KIN=THETA(1)*EXP(ETA(1)) KOUT=THETA(2)*EXP(ETA(2)) KDE=THETA(3)*EXP(ETA(3)) EDK50=THETA(4)*EXP(ETA(4)) GAMMA=THETA(5)*EXP(ETA(5)) KA=THETA(6)*EXP(ETA(6)) S2=1 ;volume of biophase fixed ;KDE IS THE ELIMINATION RATE CONSTANT FROM BIOPHASE ;IRG IS THE (VIRTUAL)INFUSION RATE IN THE INHIBITION FUNCTION ;EDK50 IS THE IR THAT LEADS TO 50% NHIBTION OF KIN $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-KDE*A(2) VIR=A(2)*KDE IRG=VIR**GAMMA COEF=1-IRG/(EDK50**GAMMA+IRG) DADT(3)=KIN*COEF-KOUT*A(3) $ERROR Y = F + F*ERR(1)+ERR(2) IPRED=F $EST METHOD=0 POSTHOC PRINT=5 MAX=9999 SIG=3 MSFO=6mp2.msf NOABORT $THETA (0.0001,0.01,10) ;[KIN] (0.0001,0.001,10) ;[KOUT] (0.01,1,100) ;[KDE] (0.1,20,100);[EDK50] (0.001,1,5) ;[GAMMA] (0.01,0.1,10) ID TIME AMT DV CMT MDV EVID SS II 1 1 0.5 . 3 1 1 . . 1 1 . 0.5 3 0 0 . . 1 8 . 2.4 3 0 0 . . 1 8 20 . 1 1 1 . . 1 14 20 . 1 1 1 1 1 1 15 . 0.4 3 0 0 . . 1 22 . 0.6 3 0 0 . . 1 29 . 0.8 3 0 0 . . 1 29 21 . 1 1 1 . . 1 35 21 . 1 1 1 1 1 1 36 . 1.4 3 0 0 . . 1 36 31 . 1 1 1 . . 1 42 31 . 1 1 1 1 1 1 43 . 0.9 3 0 0 . . 1 43 21 . 1 1 1 . . 1 49 21 . 1 1 1 1 1 1 50 . 1.7 3 0 0 . . 1 50 31 . 1 1 1 . . 1 63 31 . 1 1 1 1 1 1 64 . 0.1 3 0 0 . . 1 71 . 0.4 3 0 0 . . 1 78 . 0.6 3 0 0 . . thanks M Sarasia ____________________________________________________________________________________ Tonight's top picks. What will you watch tonight? Preview the hottest shows on Yahoo! TV. http://tv.yahoo.com/