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

From: Leonid Gibiansky <lgibiansky_at_quantpharm.com>
Date: Tue, 13 Mar 2018 21:34:21 -0400

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" <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)) * 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
>
>

Received on Tue Mar 13 2018 - 21:34:21 EDT

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