$ERROR Block: Target mediated disposition

From: "Anasuya Hazra" anasuya.h@gmail.com Subject: [NMusers] $ERROR Block: Target mediated disposition Date: Sat, 8 Apr 2006 20:38:01 -0400 Hello NONMEM Users: I am a relatively new NONMEM user working with a relatively complex model. I have a drug which upon binding to its target undergoes elimination. I have the time course of the drug as well as the target concentration, although the target time profile is quite limited. Due to this limitation and assuming quite rapid binding of the drug to the target, I am trying to use a quasi-equilibrium model (using KD for binding instead of kon and koff) of Target-mediated drug disposition [Mager and Krzyzanski, Pharm Res 22(10): 1589)]. However, I am having trouble with writing the $ERROR block where I would like to have individual predictions for both the free drug and the target. The code I have written for the model is given as following: $INPUT ID WTKG AMT RATE TIME DV MDV CMT COHT $DATA PKPD1.csv IGNORE=# $SUBROUTINES ADVAN6 TOL=5 $MODEL NCOMP=3 COMP= (CENTRAL, DEFDOSE) COMP= (PERIPH) COMP= (RETOT) $PK CL = THETA(1)*EXP(ETA(1)) ;Linear elimination constant from the central Comp VC = THETA(2)*EXP(ETA(2)) ; Volume of Central Comp KPT= THETA(3) ; C-T distribution KTP= THETA(4) ; T-C distribution KINT = THETA(5)*EXP(ETA(3)) ; Internalization Constant KDEG=THETA(6)*EXP(ETA(4)) ; Degradation rate of CD2 RO = THETA(7)*EXP(ETA(5)) ; Baseline for CD2 KD = THETA(8) ; Dissociation const for receptor KSYN = KDEG*RO S1= VC F3= RO $DES CF = 0.5*(((A(2)/VC)-A(3)-KD)+SQRT(((A(2)/VC)-A(3)-KD)**2+4*KD*A(3))) DADT(1) = -KINT*A(1)-(CL/VC+KPT-KINT)*CF*VC + KTP*A(2) DADT(2) = KPT*CF*VC - KTP*A(2) DADT(3) = KSYN-(KINT-KDEG)*(A(1)-CF*VC)-KDEG*A(3) ;CF=Free Drug (measured) ;A(1)=Total Drug (not measured) ;A(2)=Tissue Compt (not measured) ;A(3)=Target (measured) ;Initializing DADT(3) with AMT=1 in the dataset Although I have written a differential equation for the total drug, my observation is the free drug CF and I am not quite sure how do I or can I express that in the $ERROR block since the CMT argument only relates to the corresponding differential equation according to my limited knowledge about NONMEM. Any suggestion or help would be greatly appreciated. Thank you, Regards, Ana