modeling fast and slow absorption

From MAJ_Ralf_Brueckner@wrsmtp-ccmail.army.mil Mon May 8 15:10:52 1995 Subject: modeling fast and slow absorption Dear fellow NONMEM users: I am trying to model a drug where absorption from the IM depot appears to be rapid for the first 2 hours, and then slow for the remaining time. (DV includes actual drug amounts extracted/measured from IM site). I tried to switch from rapid KA to slow as follows: ********************************************************** $INPUT ID TIME AMT DV WT CMT EVID $DATA data.csv IGNORE=C $SUBROUTINE ADVAN6 TOL=3 $MODEL NCOMP=1 ; add other COMPs later COMP=(DEPOT) ; COMP=(CENTRAL) $PK KA1 = THETA(1) ; rapid KA2 = THETA(2) ; slow tka=2.5 ; or THETA(3) temp=0 IF (TIME.LT.tka) temp=1 KA=KA1*temp + KA2*(1-temp) S1=1/1000000 ; DV in ng, AMT in mg ; S2=V/1000 ; DV in ng/ml, AMT in mg $DES DADT(1) = -KA*A(1) ; DADT(2) = KA*A(1) - KEL*A(2) ********************************************************** Before TIME=tka, NONMEM/PREDPP (correctly) calculates predicted drug amount in COMP 1 (PRED) using rapid KA. But at TIME=tka, NONMEM/PREDPP suddenly starts calculating PRED as if slow KA had been used *since time=0*. Am I doing something wrong, or is there a way to get the model to take into accout that less drug is left at the depot site when slow KA starts taking effect. Thank you for your help. Ralf Brueckner