Re: Autoinduction model - An increased clearance(day 1- 14)

Shankar, A couple of thoughts that may help. (1) If the model is terminating with a note that states something along the lines of 'Infinite value of objective function', this indicates that the estimated value of TLAG for an individual is occurring at the time of a sample. Potential solutions: (a) Remove the eta from alag. With only sparse data between Day 1 and Day 14, the ability to discern individual differences in this parameter is probably limited. (b) If you do have enough data to see differences in individuals, ignore samples that occur very close to the estimated TLAG for an individual. (c) Try a different distribution for IIV of this parameter (2) Re-parameterize CLinduced vs. CLpre. There is nothing in the model or control stream that prevents CLpre > CLinduced at the typical value level or the individual level. This could occur during the search causing termination. Re-parmeterization: CLinduced = CLpre + ThetaN TVCL=CLinduced - (CLinduced - CLpre)*exp(-kout(t-tlag) becomes TVCL=CLpre + thetaN(1-exp(-kout(t-tlag)) For typical value of thetaN use a lower bound of 0 (3) The current model also assumes that all subjects have the amount of change in CLinduced vs. CLpre. So you may want to try the following which also allows the change in CL to be continuous between TIME steps. This will allow NONMEM to integrate more smoothly around time=TLAG. $PK CLP = THETA(N)*EXP(ETA(A)) CLI = THETA(N+1)*EXP(ETA(B)) ;represents the increase from CLP $DES ;T in the $DES block represents continuous time ;TIME represents the discrete time values in the input dataset CL = CLP + CLI*(1-EXP(-KOUT*(T-TLAG)) Good Luck, Luann Phillips Director, PK/PD Cognigen Corporation (716) 633-3463 ext. 236 Shankar Lanke wrote: > Dear All, > > I am working on a Pop PK data where the patients are treated with HIV drug. An autoinduction is involved with prolonged administration of the drug. An increased CL is expected from day 1 to day 14. We have intense data on day 1 and day 14 with sparse data between. Since a lag period is involved for the induction I used the equation /CL/ = /CLinduced/ -(/CLinduced - CLpre)*exp/(-/kout*(t/-/Tlag/)) described by Johan Gabrielsson as more appropriate. Also when I included a lag period for absorption in my earlier model my fits are better and OBF decreased by 200. However the final model with or without lag time for absorption + auto induction model is either terminated or covariance step is being aborted. I changed the initial estimates several times but still no luck. Though the Auto induction model aborts the fits are better than the lag time model however the estimates for Vd are 4 fold less than the expected. > > I appreciate your input and suggestions. Here is my code. > > $SUBROUTINES ADVAN13 TRANS1 TOL=5 ;(I used ADVAN6 too) > $MODEL > NPAR=9 NCOMP=4 > COMP=(DEPOT,DEFDOSE) > COMP=(LAG) > COMP=(OBSV,DEFOBS) > COMP=(PERIP) > $PK > CLP=THETA(1) > CLI=THETA(6) > KOUT=THETA(7) > TLAG=THETA(8)*EXP(ETA(6)) > > TVCL=CLI-(CLI-CLP)*EXP(-KOUT*(TIME-TLAG)) > > CL=TVCL*EXP(ETA(1)) > TVV2=THETA(2) > V2=TVV2*EXP(ETA(2)) > TVQ=THETA(3) > Q=TVQ*EXP(ETA(3)) > TVV3=THETA(4) > V3=TVV3*EXP(ETA(4)) > TVKA=THETA(5) > KA=TVKA*EXP(ETA(5)) > TVALAG1=THETA(9) > ALAG1=TVALAG1*EXP(ETA(7)) > S3=V2 > $DES > K=CL/V2 > K23=Q/V2 > K32=Q/V3 > > DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-A(2)/ALAG1 DADT(3)=A(2)/ALAG1-K23*A(3)-K*A(3)+K32*A(4) DADT(4)=K23*A(3)-K32*A(4) $ERROR > > DEL=0 > IF (F.LE.0.0001) DEL=1 > IPRE=F > W1= 1 > W2= F > IRES= DV-IPRE > IWRE=IRES/(W1+W2) > Y = F + W1*ERR(1) + W2*ERR(2) > DV2=ABS(V2-TVV2) > > $EST METHOD=1 INTERACTION PRINT=5 MAX=9999 SIG=3 MSFO=JLM.MSF $THETA (0, 6);[CLP] > > (0, 90);[V2] > (0, 19);[Q] > (0, 200);[V3] > (0, 0.16);[KA] > (0, 8);[CLI] > (0, 0.001);[KOUT] > (0, 250);[TLAG] > (0, 0.3);[ALAG1] > $OMEGA > 0.23 ;[CL] omega(1,1) > 0.18;[V2] omega(2,2) > 0 FIXED ;[Q] omega(3,3) > 0.42;[V3] omega(4,4) > 0.19;[KA] omega(5,5) > 0.09;[TLAG for Ka] > 0.1;[ALAG1 for CLI] > $SIGMA > 0.06 ;[P] sigma(1,1) > 0.09 ;[A] sigma(2,2) > $COV MATRIX=S > > Regards, > > Shankar Lanke Ph.D. University at Buffalo > > Office # 716-645-4853 > Fax # 716-645-2886 > > Cell # 678-232-3567