Re: Time-Varying Bioavailability on Zero-Order Infusion

On Tue, Mar 13, 2018, at 7:08 PM, Bill Denney wrote: > Hi Leonid, > > The biology behind it is that during a long (many day) infusion, there > appears to be adsorption to the infusion tubing and/or catheter. The real > model I'm developing is more complex in the adsorption part (there may be > saturable adsorption as shown with the dynamics in the first days), and I > want it to be accurate as a continuous time variant IV bioavailability > because I'm trying to predict different infusion rates and durations. > > The model mis-fit is both a dose-related apparent bioavailability change > (much simpler to implement than what is here) and a dose- and time-related > apparent change in bioavailability during the first portion of the dosing > due to the potential saturation of the adsorption. The kinetics after the > end of the infusion all appear to be linear over a moderate-to-large dose > range, so I don't think that it's more complex human biology. > > And for the current data set, the model runs quickly (it isn't that I'm > having to sit around forever for the solution). The technical question was > if there was some part of NONMEM that I didn't know related to controlling > infusion rates in the $DES block. (Feature request to Bob and Alison: Maybe > in NONMEM 7.5, the user could set R1 = -1 in $PK and have continuous control > of R1 in $DES-- generalized to include all compartments.) > > Thanks, > > Bill > > -----Original Message----- > From: Leonid Gibiansky <[email protected]> > Sent: Tuesday, March 13, 2018 9:34 PM > To: Sebastien Bihorel <[email protected]>; Bill Denney > <[email protected]> > Cc: NMUsers <[email protected]> > Subject: Re: [NMusers] Time-Varying Bioavailability on Zero-Order Infusion > > Hi Bill, > > I think the proposed original solution is the only one if you would like to > implement it exactly. May be it can be approximated somehow? What is the > real reason for this questions? What is the biology behind the time-variant > IV bioavailability? Or what is the model mis-fit that you are trying to fix? > > Leonid > > > > > On 3/13/2018 9:16 PM, Sebastien Bihorel wrote: > > Hi, > > > > I would suggest the following solution which should also work if you > > want to apply some covariate effect on bioavailability: > > * On the dataset side, set your RATE variable to -1 and store the > > actual infusion rates into another variable, eg IVRATE > > * On the model side: > > $PK > > ... > > > > ; assuming the IV infusion are made in compartment 1 > > F1 = <whatever time varying function> > > R1 = F1*IVRATE > > > > Voila, NONMEM should take care of the dosing in the background as usual. > > > > Sebastien > > > > ---------------------------------------------------------------------- > > -- > > *From: *"Bill Denney" <[email protected]> > > *To: *"NMUsers" <[email protected]> > > *Sent: *Tuesday, March 13, 2018 8:58:41 PM > > *Subject: *[NMusers] Time-Varying Bioavailability on Zero-Order > > Infusion > > > > Hi NONMEMers, > > > > Is there a good way to assign a time-varying bioavailabilty on a > > zero-order rate of infusion in NONMEM? The best I’ve been able to > > come up with is something like the below. It seems like something > > that should be easier than what I’m doing below (I adjusted it from > > the real example as I was typing it into the email—I could have > > introduced a bug in the process). And importantly, -9998 is well > > before any time in my database. > > > > (dosing into CMT=1 with an IV infusion) > > > > $MODEL > > > > COMP=(CENTRAL DEFDOSE DEFOBS) ; central > > > > COMP=(P1) ; peripheral 1 > > > > COMP=(P2) ; peripheral 2 > > > > $PK > > > > ; Normal stuff and ... > > > > ; Record the dosing time > > > > IF (NEWIND.LT.2) THEN > > > > TDOSE = -9999 > > > > DOSEEND = -9998 > > > > DOSE = -999 > > > > DOSERATE = 0 > > > > ENDIF > > > > IF ((EVID.EQ.1 .OR. EVID.EQ.4) .AND. RATE.GT.0) THEN > > > > TDOSE = TIME > > > > DOSEEND = TIME + AMT/RATE > > > > DOSERATE=RATE > > > > MTDIFF=1 > > > > ENDIF > > > > MTIME(1)=TDOSE > > > > MTIME(2)=DOSEEND > > > > F1 = 0 ; Bioavailability is zero so that the $DES block has full > > control over the rate. > > > > RATEADJTAU=THETA(10) > > > > RATEADJMAX=THETA(11) > > > > $DES > > > > ; Manually control the infusion > > > > RATEIN = 0 > > > > IF (MTIME(1).LE.T .AND. T.LE.MTIME(2)) THEN > > > > RATEADJCALC = RATEADJMAX * EXP(-(T – MTIME(1)) * RATEADJTAU) > > > > RATEIN = DOSERATE - RATEADJCALC > > > > ENDIF > > > > DADT(1) = RATEIN - K10*A(1) - K12*A(1) + K21*A(2) - K13*A(1) + > > K31*A(3) > > > > DADT(2) = K12*A(1) - K21*A(2) > > > > DADT(3) = K13*A(1) - > > K31*A(3) > > > > Thanks, > > > > Bill > > > > > -- Alison Boeckmann [email protected]