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RE: Variability in Dosing Rate (and amount)

From: Paul Hutson <paul.hutson>
Date: Tue, 15 Dec 2020 15:49:55 +0000

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 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 ergstrand
www.pharmetheus.com<http://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 “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 - 10:49:55 EST

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