Re: Variability in Dosing Rate (and amount)

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:* [email protected] < mailto: [email protected] > < [email protected] < mailto: [email protected] >> *On Behalf Of *Paul Hutson > > *Sent:* Tuesday, December 15, 2020 10:50 AM > > *To:* Martin Bergstrand < [email protected] < mailto: [email protected] >> > > *Cc:* [email protected] <mailto:[email protected]> > *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 < [email protected] < mailto: [email protected] >> > > *Sent:* Tuesday, December 15, 2020 8:51 AM > *To:* Paul Hutson <[email protected] <mailto:[email protected]>> > *Cc:* [email protected] <mailto:[email protected]> > *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 > > [email protected] <mailto:[email protected]> > > 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 < [email protected] < mailto: [email protected] >> wrote: > > 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