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

From: Sebastien Bihorel <sebastien.bihorel_at_cognigencorp.com>
Date: Tue, 13 Mar 2018 21:24:08 -0400 (EDT)


Hi,

As far as I know, F1 is set on dose records... any changes on sample record=
s should not affect how much drug will enter your system.

But I may be wrong...


From: "Bill Denney" <wdenney_at_humanpredictions.com>
To: "Sebastien Bihorel" <sebastien.bihorel_at_cognigencorp.com>
Cc: "NMUsers" <nmusers_at_globomaxnm.com>
Sent: Tuesday, March 13, 2018 9:21:00 PM
Subject: RE: [NMusers] Time-Varying Bioavailability on Zero-Order Infusion=
 



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 conti=
nuously vary—this solution does that, but I’d like to learn=
 a simpler way than what I suggested.



Thanks,



Bill




From: Sebastien Bihorel < [ mailto:sebastien.bihorel_at_cognigencorp.com | seb=
astien.bihorel_at_cognigencorp.com ] >
Sent: Tuesday, March 13, 2018 9:17 PM
To: Bill Denney < [ mailto:wdenney_at_humanpredictions.com | wdenney_at_humanpred=
ictions.com ] >
Cc: NMUsers < [ mailto:nmusers_at_globomaxnm.com | nmusers_at_globomaxnm.com ] >=
 
Subject: Re: [NMusers] Time-Varying Bioavailability on Zero-Order Infusion=
 





Hi,





I would suggest the following solution which should also work if you want t=
o apply some covariate effect on bioavailability:


* On the dataset side, set your RATE variable to -1 and store the actual in=
fusion 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" < [ mailto:wdenney_at_humanpredictions.com | wdenney_at_human=
predictions.com ] >
To: "NMUsers" < [ mailto:nmusers_at_globomaxnm.com | 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 easie=
r 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 th=
e 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 - 21:24:08 EDT

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