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

From: Bill Denney <wdenney_at_humanpredictions.com>
Date: Tue, 13 Mar 2018 21:21:00 -0400

Hi Sebastien,


Thanks for that suggestion!



Unfortunately, that will only update when I have observation records, so it
will change R1 in discrete steps at each observation (I could insert a lot
of observations, but it still has the same limitation). I need it to
continuously vary—this solution does that, but I’d like to =
learn a simpler
way than what I suggested.



Thanks,



Bill



*From:* Sebastien Bihorel <sebastien.bihorel_at_cognigencorp.com>
*Sent:* Tuesday, March 13, 2018 9:17 PM
*To:* Bill Denney <wdenney_at_humanpredictions.com>
*Cc:* NMUsers <nmusers_at_globomaxnm.com>
*Subject:* Re: [NMusers] Time-Varying Bioavailability on Zero-Order Infusio=
n



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 wit=
h 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 proce=
ss).
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 contro=
l
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 - 21:21:00 EDT

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