From: Leonid Gibiansky <*lgibiansky*>

Date: Tue, 15 Dec 2020 11:59:13 -0500

not sure the code is correct for 3 days case

As written, it assumes that FDAY1=0.5, FDAYS2=1/4, FDAYS3=1/4 (on average)

Possible way to code this type of fractions is

FF2=THETA()*EXP(ETA())

FF3=THETA()*EXP(ETA())

F1= 1/(1+FF2+FF3)

F2= FF2/(1+FF2+FF3)

F3= FF3/(1+FF2+FF3)

Leonid

On 12/15/2020 11:31 AM, Bill Denney wrote:

*> Hi Paul,
*

*>
*

*> Martin’s ideas are great ones. My first thought on the “clever coding”
*

*> would be to treat it like bioavailability. You should be sure that you
*

*> split it between days rather than estimate it completely separately
*

*> between days. I would think of doing it in general like:
*

*>
*

*> ; Fraction of chow consumed on the first day
*

*>
*

*> FDAY1 = 1/(1+EXP(-ETA(1))
*

*>
*

*> ; Fraction of chow consumed on the second and third days if there are
*

*> only two days of dosing
*

*>
*

*> IF (NDAYS.EQ.2) THEN
*

*>
*

*> FDAY2=1-FDAY1
*

*>
*

*> FDAY3=0
*

*>
*

*> ENDIF
*

*>
*

*> ; Fraction of chow consumed on the third day
*

*>
*

*> IF (NDAYS.EQ.3) THEN
*

*>
*

*> FDAY2=(1-FDAY1)*(1/(1+EXP(ETA(2))))
*

*>
*

*> FDAY3=1-FDAY1-FDAY2
*

*>
*

*> ENDIF
*

*>
*

*> IF (CHOWDAY.EQ.1) F1=FDAY1
*

*>
*

*> IF (CHOWDAY.EQ.2) F1=FDAY2
*

*>
*

*> IF (CHOWDAY.EQ.3) F1=FDAY3
*

*>
*

*> What the code does is ensure that the total dose among days is not
*

*> greater than the total dose measured. (Note that the code was typed
*

*> directly into the email—there could be a typo in it, but it gives the
*

*> intent.) It assumes that the dataset has columns setup as:
*

*>
*

*> * AMT: the total dose as measured across the 2 or 3 days (not divided by
*

*> the number of days)
*

*>
*

*> * NDAYS: the number of days where AMT was measured (i.e. 2 if it was
*

*> measured over 2 days and 3 if it was measured over three days)
*

*>
*

*> * CHOWDAY: The day number in the set of days when AMT is measured (1, 2,
*

*> or 3)
*

*>
*

*> It requires that your ETAs are setup for inter-occasion variability (you
*

*> can find many examples of that with a web search). It also requires
*

*> that you have a measurement or two of PK between each of these doses so
*

*> that the ETA values are estimable. If you do not have PK between two
*

*> doses (e.g. after the dark period for Day 1), you may not be able to
*

*> estimate ETA for that dose.
*

*>
*

*> Thanks,
*

*>
*

*> Bill
*

*>
*

*> *From:*owner-nmusers *

*> <mailto:owner-nmusers *

*> <mailto:owner-nmusers *

*> *Sent:* Tuesday, December 15, 2020 10:50 AM
*

*> *To:* Martin Bergstrand <martin.bergstrand *

*> <mailto:martin.bergstrand *

*> *Cc:* nmusers *

*> *Subject:* RE: [NMusers] Variability in Dosing Rate (and amount)
*

*>
*

*> Thank you, Martin. That is a great idea, yet I think you give me too
*

*> much credit to expect “clever coding”.
*

*>
*

*> I’ll report back. Be well.
*

*>
*

*> Paul
*

*>
*

*> Paul Hutson, PharmD, BCOP
*

*>
*

*> Professor
*

*>
*

*> UWisc School of Pharmacy
*

*>
*

*> T: 608.263.2496
*

*>
*

*> F: 608.265.5421
*

*>
*

*> *From:*Martin Bergstrand <martin.bergstrand *

*> <mailto:martin.bergstrand *

*> *Sent:* Tuesday, December 15, 2020 8:51 AM
*

*> *To:* Paul Hutson <paul.hutson *

*> *Cc:* nmusers *

*> *Subject:* Re: [NMusers] Variability in Dosing Rate (and amount)
*

*>
*

*> Dear Paul,
*

*>
*

*> I'm sorry for the late answer. Maybe you have already solved this issue
*

*> by now?
*

*>
*

*> The approach that I would suggest is to implement the ingestion of the
*

*> dose as a zero-order infusion with an estimated duration and start.
*

*>
*

*> 1. Set the dose time to the start of the 12 h dark period.
*

*> 2. Set the AMT data item to the total ingested drug amount.
*

*> 3. Set RATE data item to '-2' (=> estimation of duration (D) of
*

*> infusion into compartment, D1 for CMP=1)
*

*> 4. Assuming that the dose is entered into CMT=1 you can in the NONMEM
*

*> control file estimate ALAG1 and D1 governing the start and duration
*

*> of an assumed constant ingestion.
*

*> Note: you can consider different types of clever coding to limit the
*

*> total ingestion within the 12 h dark period if you want.
*

*>
*

*> This will of course be an approximation as the ingestions likely isn't
*

*> constant. It should however be sufficiently flexible to fit your data
*

*> without biasing assumptions of total dose/exposure.
*

*>
*

*> Kind regards,
*

*>
*

*> Martin Bergstrand, Ph.D.
*

*>
*

*> Principal Consultant
*

*>
*

*> Pharmetheus AB
*

*>
*

*> martin.bergstrand *

*>
*

*> www.pharmetheus.com <http://www.pharmetheus.com/>
*

*>
*

*> /This communication is confidential and is only intended for the use of
*

*> the individual or entity to which it is directed. It may contain
*

*> information that is privileged and exempt from disclosure under
*

*> applicable law. If you are not the intended recipient please notify us
*

*> immediately. Please do not copy it or disclose its contents to any other
*

*> person./
*

*>
*

*> On Thu, Dec 10, 2020 at 5:32 AM Paul Hutson <paul.hutson *

*> <mailto:paul.hutson *

*>
*

*> Dear Users, I hope that someone can suggest a paper or method for
*

*> addressing an issue with which I am grappling.
*

*>
*

*> I am working on a mouse toxicokinetic study that has two basic
*

*> cohorts. One received a bolus gavage dose of known dose and time.
*

*> The other was dosed by drug-laden chose. The chow and thus drug
*

*> ingested was measured, usually daily in the morning, but sometimes
*

*> after 2-3 days. The “daily dose” of chow was averaged over the 12
*

*> hours of the daily dark period in which the animals were considered
*

*> to be eating their chow. 2-3 blood samples were obtained from each
*

*> animal, and the basic 2 compartmental SEAM IMP method is converging
*

*> well on the gavage-only data.
*

*>
*

*> Can the group suggest how to address the uncertainty in the rate of
*

*> dosing over the 12 hour dark period? Of additional concern, hard to
*

*> deal with, is the potential that nightly chose ingestion varied over
*

*> a series of 1-3 days. I don’t think that the 12 August 2020 thread
*

*> on a random effect on ALAG applies to this case.
*

*>
*

*> Many thanks.
*

*>
*

*> Paul
*

*>
*

*> Paul Hutson, PharmD, BCOP
*

*>
*

*> Professor
*

*>
*

*> UWisc School of Pharmacy
*

*>
*

*> T: 608.263.2496
*

*>
*

*> F: 608.265.5421
*

*>
*

Received on Tue Dec 15 2020 - 11:59:13 EST

Date: Tue, 15 Dec 2020 11:59:13 -0500

not sure the code is correct for 3 days case

As written, it assumes that FDAY1=0.5, FDAYS2=1/4, FDAYS3=1/4 (on average)

Possible way to code this type of fractions is

FF2=THETA()*EXP(ETA())

FF3=THETA()*EXP(ETA())

F1= 1/(1+FF2+FF3)

F2= FF2/(1+FF2+FF3)

F3= FF3/(1+FF2+FF3)

Leonid

On 12/15/2020 11:31 AM, Bill Denney wrote:

Received on Tue Dec 15 2020 - 11:59:13 EST