# Re: Variability in Dosing Rate (and amount)

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

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