Time-varying input/flexibility to change input rate on the fly

Hi Robin, I don't think that I've seen an update. That said, the need I had then was for a very specific need for an unusual drug. I've only seen this type of issue once where it seemed to need time-dependent effects. Generally, effects similar-- but not identical-- to what I was experiencing at the time are better-modeled with simpler systems. For example, adsorption to infusion sets can almost always be modeled as a decrease in bioavailability and/or a lag time (it's not typically time-dependent behavior). I would assume that loss of part of a tablet or detachment of a patch could be simply modeled as random variability (or a fixed effect) on bioavailability. Random pump malfunction would depend on how it malfunctioned, but I would be wary of trying to model random effects as this more complex time-dependent bioavailability unless you had data on the malfunction method-- in which case I would suggest putting it into the dataset as a different dosing record. Thanks, Bill

Hi Bill, Thank you for your quick answer. As far as I understand Nonmem's inner workings, bio availability is only applied at the onset of dosing and adding variability on it would not be able to capture a transient change in input. For example in the case of a patch, if it would detach partly during the dosing interval one would still need an input (i.e. infusion-style input in the depot) but it would just be lower than before. Changing F1 would in this case not do much right? Kind regards, Robin Dr. ir. Robin Michelet Senior scientist Freie Universitaet Berlin Institute of Pharmacy Dept. of Clinical Pharmacy & Biochemistry Kelchstr. 31 12169 Berlin Germany Phone: + 49 30 838 50659 Fax: + 49 30 838 4 50656 Email: robin.michelet www.clinical-pharmacy.eu https://fair-flagellin.eu/

one can do it by hands, like set F1=1 and then use DA1/dt = -KA*A(1) DA2/dt = FF1(any function of time)*A(1) .. will it do the trick? Leonid

Hi Robin, I have used the DECLARE option in the $ABBREVIATED block to initialize DOSE as a global variable. Then I used MTIME()/MPAST() to flexibly deliver dose into a DEPOT compartment from a patch, assuming different infusion durations after detachment and reattachment of the patch. See the code below. Best Eliford ``` $PROBLEM One compartment model with erratic absorption from a patch $INPUT ID TIME DV AMT CMT EVID MDV $DATA ../data/erratic_patch.csv IGNORE $SUBROUTINE ADVAN6 TRANS1 TOL=6 $MODEL COMP = (DEPOT) COMP = (CENTRAL) COMP = (ADMINDOSE) ;; Accumulate total dose delivered to depot compartment $ABBR DECLARE DOSE(10) ;; Declare DOSE as a global variable with 10 dimensions as place holder $THETA (0, 0.3) ; KA (0, 3) ; CL (0, 15) ; Vc (0, 3) ; DT1 ;; Detach and re-attach time can be estimated (0, 6) ; DT2 ;; (0, 15) ; DD1 (0, 12) ; DD2 ;; Variable durations of zero order delivery to depot compartment can be estimated (0, 4) ; DD3 (0, 1) ; ADD (0, 0.1) ; PROP $OMEGA BLOCK(1) 0.1 ; EKA $OMEGA BLOCK(1) 0.1 ; ECL $OMEGA BLOCK(1) 0.1 ; EVC $OMEGA BLOCK(1) 0.1 ; EDT1 $OMEGA BLOCK(1) 0.1 ; EDT2 $OMEGA BLOCK(1) 0.1 ; EDD1 $OMEGA BLOCK(1) 0.1 ; EDD2 $OMEGA BLOCK(1) 0.1 ; EDD3 $SIGMA 1 FIX $PK TVKA = THETA(1) ; Absorption rate constant from depot TVCL = THETA(2) ; Clearance from central cmpt TVVC = THETA(3) ; Distribution volume of central cmpt TVDT1 = THETA(4) ; Detach time 1 TVDT2 = THETA(5) ; Detach time 2 TVDUR1 = THETA(6) ; Delivery duration 1 TVDUR2 = THETA(7) ; Delivery duration 2 TVDUR3 = THETA(8) ; Delivery duration 2 KA = TVKA * EXP(ETA(1)) ; CL = TVCL * EXP(ETA(2)) ; VC = TVVC * EXP(ETA(3)) ; DT1= TVDT1 * EXP(ETA(4)) ; DT2= TVDT2 * EXP(ETA(5)) ; DUR1= TVDUR1 * EXP(ETA(6)) ; DUR2= TVDUR2 * EXP(ETA(7)) ; DUR3= TVDUR3 * EXP(ETA(8)) ; K = CL/VC ; F1 = 0 ; Prevent NONMEM from adding dose into depot ADMDOSE = A(3) ; Total Dose delivered to depot compartment at any time after dose MTIME(1) = DT1 ; Model event time for detachment MTIME(2) = DT2 ; MOdel event time for reattachment IF(EVID.EQ.1) THEN DOSE(1) = AMT ; Give value to the global dose variable created with $ABBR DECLARE ENDIF $DES DOSE1 = DOSE(1) ; Make the dose global RATE1 = DOSE1/DUR1 ; Initial rate of drug delivery into depot cmpt IF(T.GE.DT1) THEN DOSE2 = DOSE(2) ; Remaining dose in the patch just before detachment RATE2 = DOSE2/DUR2 ; rate of drug delivery into depot cmpt after detach 1 ENDIF IF(T.GE.DT2) THEN DOSE3 = DOSE(3) ; Remaining dose in the patch just before re-attachment RATE3 = DOSE3/DUR3 ; rate of drug delivery into depot after reattachment ENDIF RATE = RATE1 * (1 - MPAST(1)) ; FLEXIBLE RATE BASED ON MODEL EVENT TIMES RATE = RATE + RATE2 * (MPAST(1) - MPAST(2)) ; RATE = RATE + RATE3 * MPAST(2) ; IF(ADMDOSE.GT.DOSE1) RATE= 0 ; Switch off delivery to depot when all dose has been consumed ADMDOSE1 = RATE1*DT1 ; Calculate remaining dose in the patch ADMDOSE2 = RATE2*(DT2-DT1) ; DOSE(2) = DOSE1 - ADMDOSE1 ; DOSE(3) = DOSE1 - (ADMDOSE1+ADMDOSE2) ; DADT(1) = RATE - KA*A(1) ; Differential equations DADT(2) = KA*A(1) - K*A(2) ; DADT(3) = RATE ; $ERROR IPRED = F ; CENTRAL is default observation compartment ADD = THETA(9) ; Additive residual PROP = IPRED * THETA(10) ; Prop residual W = SQRT(ADD**2 + PROP**2) ; Weighting factor Y = IPRED + W*EPS(1) ; IRES = DV-IPRED IWRES = IRES/W DEPOTA = A(1) NREPLICATE = NREP IREPLICATE = IPRED $SIMULATION (82536690) SUBPROBLEM=1 ONLYSIMULATION $TABLE ID TIME DV IPRED EVID KA CL VC DT1 DT2 DUR1 DUR2 DUR3 RATE1 RATE2 RATE3 RATE DOSE1 DOSE2 DOSE3 DEPOTA ADMDOSE NREPLICATE IREPLICATE NOPRINT ONEHEADER APPEND FILE=MYTAB1 ``` Simulation dataset patchdata <- expand.grid(ID=1, TIME=seq(0, 48, 1), DV=".") %>% mutate(AMT=ifelse(TIME=0, 10, NA), CMT= ifelse(TIME=0, 1, 2), EVIDifelse(TIME=0, 1, 2), MDV=1)