Is “DOSE=0” accepted by NONMEM?

Dear NONMEM users, I have a group of patients, whose plasma drug levels are measured and known at time=0 (no further drug is given to the patients afterwards.). I try to know, after how long time the drug will be completely cleared out from these patients. Naturally I used NONMEM to fit the patients' V and CL, in order to get plasma concentration change profile. However seems NONMEM only accepts DOSE is a positive number. If DOSE=0, NONMEM can't perform the fitting. Can anyone kindly give me some suggestions to solve this problem? Thanks a lot in advance! PTID DV AMT time EVID 2 . 0 0 1 2 6.8 0 0 0 2 1.1 0 3 0 2 0 0 6 0 3 . 0 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 Zheng

Dear Zheng, NONMEM wants an amount there, or it won't interpret that record as a dose. On the other hand, if you don't put anything into the system, or you do not initialise the compartments (see below), nothing is going to happen. If you want to use a dose to initialise the system, them you can put AMT=1 and use the bioavailability parameter to decide how much to put it F1= YYY. YYY can be then be a number in the data or a parameter. If you want to use parameters, I suggest that you look into how to model baselines Dansirikul C, Silber HE, Karlsson MO. 2008. Approaches to handling pharmacodynamic baseline responses. J. Pharmacokinet. Pharmacodyn. 35:269–283. In the same paper there are also snippets of code on how to initialise compartments with the command A_0(1) = YYY which is a somewhat neater option. I would prefer the second option A_0_1, but I guess if you use some of the basic ADVANs, NONMEM may expect a dose and give you an error if it doesn't find one. Good luck. Paolo

On 9/7/2015 8:30, Zheng Liu wrote: > However seems NONMEM only accepts DOSE is a positive number. If DOSE=0, > NONMEM can't perform the fitting. Can anyone kindly give me some > suggestions to solve this problem? Thanks a lot in advance! You could set EVID=2 instead of 1 in the records with TIME=0 and AMT=0. -- Paul Matthias Diderichsen, PhD Quantitative Solutions B.V. +31 624 330 706

Zheng, If you have only subjects with unknown dosing history, one can assume mono-exponential decay (provided that the data do not contradict this assumption: can be checked by plots of DV vs TIME in semi-scale). With this assumption, one can use $PRED C0 = THETA(1)*EXP(ETA(1)) ; initial value K = THETA(2)*EXP(ETA(2)) ; rate of decay TY = C0*EXP(-K*TIME) ; individual prediction Y = TY*(1+EPS(1)) ; proportional error model Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566

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