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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

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