Modeling Rates and Effects of Drug X

I thought perhaps others might be interested in the following exchange - I've disguised the drug/firm/person in case there's a confidentiality issue. =================================================================== ----- Begin Included Message ----- Dear Dr. Sheiner, Using NONMEM, I am seeking to model the serum concentration of endogenous substance X in response to multiple doses of a drug that affects X. The model we're employing is a one-compartment model with first-order elimination of X and zero-order (endogenous) input of X. The drug is hypothesized to alter the elimination rate constant and/or the input rate. So there are four parameters we seek to estimate: 1) X input rate while on drug 2) X input rate while off drug 3) X elimination rate constant while on drug 4) X elimination rate constant while off drug My question is this: it seems that in order to estimate the X input rates, we need to specify the total amount of X the body produces for the duration of the study. The total amount produced is, of course, unknown: the best we can do is to make an educated guess as to the total amount. Is there any way around this problem- namely, is it possible to estimate both the X input rates and the total amount of X produced? Any guidance you can provide us with respect to this problem would be gratefully appreciated. Thank you for your attention to this matter. Sincerely yours, A Nonmem User ----- End Included Message ----- I think your problem is very simple and you are not aware of the capacity to model the rate of an infusion. Taking you literally, you seem to have only 2 conditions, off drug (ONDR=0) and on drug (ONDR=1). If so, then you can do your problem with ADVAN1 using a $PK something like $PK KK = THETA(1) ; OFF-DRUG TV ELIM RATE IF(ONDR.EQ.1) KK = THETA(2) ; ON-DRUG TV ELIM RATE K = KK*(1+ETA(1)) ; ON-DRUG INDIVIDUAL ELIM RATE RR = THETA(3) ; OFF-DRUG TV INPUT RATE IF(ONDR.EQ.1) RR = THETA(4) ; ON-DRUG TV INPUT RATE R1 = RR*(1+ETA(2)) ; ON-DRUG INDIVIDUAL INPUT RATE Your input record would be $INPUT ID TIME AMT RATE ONDR X=DV and the first record of each subject would specify an infusion of "infinite" total amount of X which enters at a modeled rate (R1 in $PK). Your data file might then start (if # was named as IGNORE=# on your data record), as: #ID TIME AMT RATE ONDR X=DV 1 0 9999 -1 0 . etc. Note: 1.You can see that it would be easy to substitute a "dose-response" function (e.g., linear) for the in or out-rates if you had a DOSE (of drug) column in the data. 2. If you wanted to write a PK/PD model with PK of drug and kinetics of X affected by drug, you could do so using the same input trick, but of couse, you'd have to write your model using ADVAN6 or higher (since out rate of X would be the scaled product of drug concentration times X concentration). 3. ONDR must have the correct value on every record the way I've written $PK because K and R1 are recomputed at every time depending on its value. Good luck, LBS.