Re: Is “DOSE=0” accepted by NONMEM?

Hi Zheng, Leonid Gibiansky answered your email suggeting a non-compartmental $PRED. Paolo Denti gave some other ideas, including initialization of compartment 1 with the observed value using A_0(1). I have a different suggestion. If the drug is oral, then there is still drug in the depot at TIME=0. Please look at the help item for EXOGENOUS SUPPLEMENTATION EXAMPLE. The paragraph starting "For the drug with unknown dosing history" is the one of interest. A Steady-state infusion into the depot,ending at time 0, with a rate modelled by a theta is used. NONMEM will adjust the theta to best fit not only the "baseline" observation at time 0, but also the later observations. I've taken your fragment of data and called it dose0ss.dat I made up a little ADVAN2 control stream called dose0ss.ctl. NONMEM does a reasonable job of finding a minimum with this fragment. Here is dose0ss.dat @PTID DV AMT time EVID SS II RATE 2 . 0 0 1 1 0 -1 2 6.8 0 0 0 . . . 2 1.1 0 3 0 . . . 2 0 0 6 0 . . . 3 . 0 0 1 1 0 -1 3 1.08 0 0 0 . . . 3 0.16 0 3 0 . . . 3 0.03 0 6 0 . . . 3 0 0 9 0 . . . Here is dose0ss.ctl $PROBLEM Example of pre-existing drug. $INPUT ID DV AMT TIME EVID SS II RATE $DATA dose0ss.dat IGNORE=@ $SUBROUTINES ADVAN2 TRANS2 $PK KA=THETA(1)*EXP(ETA(1)) V=THETA(2)*EXP(ETA(2)) S2=V CL=THETA(3)*EXP(ETA(3)) R1=THETA(4)*EXP(ETA(4)) $ERROR A1=A(1) A2=A(2) C2=A2/V IPRED=F Y=F+ERR(1) $THETA (0,2) (0,1) (0,1) (0,1) $OMEGA 1 1 1 1 $SIGMA 1 $ESTIM METHOD=1 $TABLE ID TIME A1 C2 IPRED NOPRINT FILE=dose0ss.tbl LFORMAT="(20(4X,A8))" The first 6 columns of the table are as follows. In the table, IPRED and C2 are computed with individual etas. Note that they are identical and closely match the DV values at TIME=0. TABLE NO. 1 ID TIME A1 C2 IPRED DV 2.0000E+00 0.0000E+00 4.0371E+00 6.8010E+00 6.8010E+00 0.0000E+00 2.0000E+00 0.0000E+00 4.0371E+00 6.8010E+00 6.8010E+00 6.8000E+00 2.0000E+00 3.0000E+00 1.5287E-01 1.0877E+00 1.0877E+00 1.1000E+00 2.0000E+00 6.0000E+00 5.7889E-03 7.1662E-02 7.1662E-02 0.0000E+00 3.0000E+00 0.0000E+00 6.4092E-01 1.0795E+00 1.0795E+00 0.0000E+00 3.0000E+00 0.0000E+00 6.4092E-01 1.0795E+00 1.0795E+00 1.0800E+00 3.0000E+00 3.0000E+00 2.4242E-02 1.7236E-01 1.7236E-01 1.6000E-01 3.0000E+00 6.0000E+00 9.1695E-04 1.1333E-02 1.1333E-02 3.0000E-02 3.0000E+00 9.0000E+00 3.4683E-05 6.0484E-04 6.0484E-04 0.0000E+00