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Re: Variability in Dosing Rate (and amount)

From: Martin Bergstrand <martin.bergstrand>
Date: Tue, 15 Dec 2020 15:51:10 +0100

Dear Paul,

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

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=
   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=
   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


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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 =
> dose” of chow was averaged over the 12 hours of the daily dark pe=
riod 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 SEA=
> IMP method is converging well on the gavage-only data.
> Can the group suggest how to address the uncertainty in the rate of dosin=
> over the 12 hour dark period? Of additional concern, hard to deal with, =
> 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 e=
ffect 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 - 09:51:10 EST

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