Re: [NMusers] Time-Varying Bioavailability on Zero-Order Infusion

From: Alison Boeckmann <alisonboeckmann_at_fastmail.fm>
Date: Thu, 15 Mar 2018 17:43:19 -0700

I'll take a look at it.

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 w=
as
> 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: Ma=
ybe
> in NONMEM 7.5, the user could set R1 = -1 in $PK and have continuous co=
ntrol
> of R1 in $DES-- generalized to include all compartments.)
>
> Thanks,
>
> Bill
>
> -----Original Message-----
> From: Leonid Gibiansky <lgibiansky_at_quantpharm.com>
> Sent: Tuesday, March 13, 2018 9:34 PM
> To: Sebastien Bihorel <sebastien.bihorel_at_cognigencorp.com>; Bill Denney
> <wdenney_at_humanpredictions.com>
> Cc: NMUsers <nmusers_at_globomaxnm.com>
> 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-varia=
nt
> IV bioavailability? Or what is the model mis-fit that you are trying to f=
ix?
>
> 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" <wdenney_at_humanpredictions.com>
> > *To: *"NMUsers" <nmusers_at_globomaxnm.com>
> > *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)) * RATEADJ=
TAU)
> >
> > 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
  alisonboeckmann_at_fastmail.fm

Received on Thu Mar 15 2018 - 20:43:19 EDT

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