$ERROR block TMDD

Hello NONMEM Users, I’m relatively new NONMEM user. I have a drug which has showed TMDD (QSS) elimination in a previous study. In that study the drug binds to its target in central compartment. I only have the time course of the drug concentration. I tried to test the same model as well as Michaelis-Menten(MM)approach in my study but I failed. Reading some papers (Wan-Su Park et al, 2017Doi: 10.1111/bcpt.12675; P Dua et al, 2015 doi:10.1002/psp4.41 ), I found that the drug can only binds to its target in peripheral compartment or in both compartments at the same time. I want to try these models but I have trouble writing the $ERROR block. The code I have written for the model in which the drug binds to its target in peripheral compartment is given as following: $INPUT ID TIME AMT TINF RATE DV TAD MDV EVID $DATA ADPKD_100918.csv $SUBROUTINE ADVAN13 TOL=9 $MODEL COMP=(CENTRAL) COMP=(PERIPH1) COMP(PERIPH2) $PK TVCL=THETA (1) ;Linear elimination constant from the central Comp TVV1=THETA(2) ; Volume of Central Comp TVQ = THETA(3) ; Distributional clearance TVV2 = THETA(4) ; tissue distribution volumes TVKM= THETA (5) ; MM constant TVVM= THETA(6) ; Vmax TVKINT = THETA (7) ; Internalization constant TVKSYN = THETA(8) ; Synthesis rate constant TVKDEG = THETA(9) ; Degradation rate constant CL = TVCL*EXP(ETA(1)) V1 = TVV1*EXP(ETA(2)) Q = TVQ ;*EXP(ETA(3)) V2 = TVV2;*EXP(ETA(4)) KSS = TVKSS;*EXP(ETA(5)) KINT = TVKINT KSYN = TVKSYN KDEG = TVKDEG K = CL/V1 ; elimination rate constant K12 = Q/V1 ; central-tissue rate constant K21 = Q/V2 ;tissue-central rate constant S1 = V1 BASE = KSYN/KDEG ; baseline for target A_0(3) = BASE $DES CONC=0.5*(A(2)/V2-A(3)-KM)+0.5*SQRT((A(2)/V2-A(3)-KM)**2+4*KSS*A(2)/V2) DADT(1) = -(K+K12)*A(1)+K21*CONC*V2 DADT(2) = K12*A(1)- K21*CONC*V2 - KINT*A(3)*CONC*V2/(KSS+CONC) DADT(3) = KSYN - KDEG*A(3) - (KINT-KDEG)*CONC*A(3)/(KSS+CONC) ; CONC = Concentration of free drug in peripheral comp (not measured) ; A1 = Free drug in Central Compart (not measured) ;A2 = Free Drug second compartment amount (not measured) ; A3 = Target (not measured) Although I have written a differential equation for the total drug in peripheral compartment, but I have only measured the free drug concentration in central compartment. I’m not sure how can I write that in the $ERROR block. Any suggestion or help will be gratefully received Regards, Niurys de Castro Suárez -- MSc Niurys de Castro Suárez Profesor Asistente Farmacocinética/Biofarmacia Investigador Agregado Departamento Farmacia Instituto de Farmacia y Alimentos, Universidad de La Habana Cuba "Una estrella brilla en la hora de nuestro encuentro"

You should not expect dramatic differences between the model with central binding and peripheral binding. So if the model failed (completely failed ? or just not good enough?), this is for some other reasons. You may want to start with the simple linear model, find parameters, then add Michaelis-Menten part, and only then move to the QSS model. On each stage, start with the parameters of the best model of the previous stage. To answer your specific question, equations and error block are two independent parts of the model, so you just use Y=A(1)/V1*(1+EPS) ; measured: free drug in central compartment (if proportional error model is used). Note that KM is not defined but used instead of KSS in some places, could it be the reason for failure? TVKSS is not defined but used... Regards, Leonid