How does NONMEM $DES work?

From: "Wang, Yaning" WangYA@cder.fda.gov Subject: [NMusers] How does NONMEM $DES work? Date: Tue, December 21, 2004 7:46 pm Dear all: I am using an indirect model to describe the profile of an endogenous compound (A). And the elimination of this compound is affected by the exposure of a drug (B). Since it is almost impossilbe to find a model to describe the time course of drug B and there are enough pairs of drug B concentration and compound A level, I want to use the observed drug B concentration in the indirect model as follows: $DES DADT(1)=K0-KE{1+EMAX*C/(EC50+C)}*A(1) where C is the observed drug B concentration and A(1) is the endogenous compound level. I am concerned about how NONMEM handles this differential equations during the time interval where there are no inputs for C. For example, if we have data rows at day 1 and day 2 (for both A and B), how can NONMEM fit compound A level at day 2 without the drug B level information (C) during the interval between day 1 and day2? Is NONMEM assuming some interpolated values for C based on C1 and C2? If this approach is wrong, then consider another case. Suppose clearance (CL) follows a covariate model, e.g. CL=THETA(1)*(WT/70)**THETA(2). CL=THETA(1)*(WT/70)**THETA(2)*EXP(ETA()) $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-CL*A(2) Even though we have the same body weight at each row for one subject, how can NONMEM know WT is not a time dependent covariate? What if WT IS a time dependent covariate? Has anyone used the covariate model this way(or in a closed-form equation pattern)? Thanks a lot for any comment. Yaning Wang, PhD Pharmacometrician OCPB, FDA