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RE: Variability in Dosing Rate (and amount)

From: Bill Denney <wdenney>
Date: Tue, 15 Dec 2020 11:31:13 -0500

Hi Paul,



Martin’s ideas are great ones. My first thought on the “cl=
ever 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.) I=
t
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
Behalf Of *Paul Hutson
*Sent:* Tuesday, December 15, 2020 10:50 AM
*To:* Martin Bergstrand <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
*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 infusi=
on
   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 a=
n
   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



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On Thu, Dec 10, 2020 at 5:32 AM Paul Hutson <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 “d=
aily
dose” of chow was averaged over the 12 hours of the daily dark peri=
od 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 eff=
ect 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 - 11:31:13 EST

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