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Re: Weird behavior (or poor understanding on my side) of the SS=2 option

From: Alison Boeckmann <alisonboeckmann>
Date: Fri, 09 Oct 2009 12:10:06 -0700

Paolo is correct in his understanding.
A bug was introduced into PREDPP when the Initial Steady State feature
was introduced, in NONMEM VI 2.0.
SS=2 doses do not work correctly. This same bug is present in NONMEM 7.
More details will be sent when available.

On Mon, 05 Oct 2009 09:37:05 +0200, "Paolo Denti"
<paolo.denti
> Dear all,
> I am creating a dataset with the SS=2 option and I noticed an unexpected
> prediction profile that indicated that I am misinterpreting the way SS
> works in NONMEM... I would appreciate any feedback.
>
> My understanding of the SS option in NONMEM is that the dose is assumed
> as previously given at regular intervals (specified by II), and the
> level of drug concentration resulting from this process is calculated.
> There are different options (1, 2 and 3), which I list below to clarify
> the way I understand them to work, so that it might be clear where I am
> mistaken.
>
> According to the NONMEM guide, SS=1 should zero-out all system
> compartments and reset them to the value resulting only from the
> steady-state dose, thus virtually forgetting the past dosing history
> completely, with the exception of the steady-state dose and its previous
> infinite homologous doses. SS=3 - besides all the Greek in the
> explanation - seems to be doing the same, but using different values for
> the initial estimates (?!?). In any case, I tried and it zeroes-out the
> compartments as SS=1 does.
>
> SS=2, instead, is supposed to calculate the steady-state level of drug
> resulting from the implied series of doses, and add that amount ON TOP
> of whatever other amount would be in the compartments resulting from
> extra sources, i.e., I would add, other amounts present in the
> compartments due to events PRIOR to the SS=2 record.
>
> I want to build an integrated model to analyze multiple drugs at the
> same time, so I would avoid the SS=1 option, as the doses for drug x
> would cancel out the ones for drug y... So I used SS=2, but it behaves
> in a way I did not expect.
>
> I have dosing history for three days before the experiment, but not for
> all patients. The drug is given once daily, normally in the morning, but
> the exact time generally changes from day to day, so I decided to model
> the first dose I have record of as steady-state, and then follow the
> dosing history. Some subjects, however, always declared to have taken
> the dose at 8 am. I pasted a fragment of the dataset below.
>
> #ID TIME DV AMT SS II MDV
> 1 0 . 450 2 24 1
> 1 24 . 450 0 . 1
> 1 48 . 450 0 . 1
> 1 72 . 450 0 . 1
> 1 72.2 0.05 . . . 0
> 1 73.3 3.83 . . . 0
> 1 74.4 3.27 . . . 0
> 1 75 2.66 . . . 0
> 1 96 . . . . 1
>
> I would expect to observe the very same predictions at 24 hours
> distance, as 24 hours is the inter-dose interval.
> However, after a minimization successful and that's what I get as an
> output:
> ID TIME Y DV PRED RES WRES IPRE IRES IWRE
> 1 0 */0.11356 /* 0 0.16226 0 0 */0.11356/*
> -0.11356 -0.090191
> 1 24 */0.11356/* 0 0.16226 0 0 */0.11356/*
> -0.11356 -0.090191
> 1 48 */0.056889/* 0 0.081288 0 0 */0.056889/*
> -0.056889 -0.045196
> 1 72 */0.056782/* 0 0.081132 0 0 */0.056782 /*
> -0.056782 -0.045111
> 1 72.2 0.59151 0.05 0.81647 -0.76647 -0.4746
> 0.59151 -0.54151 -0.42489
> 1 73.3 2.557 3.83 3.5268 0.30316 0.49445 2.557
> 1.273 0.83272
> 1 74.4 3.3771 3.27 4.6667 -1.3967 -0.27596
> 3.3771 -0.10714 -0.062947
> 1 75 3.5245 2.66 4.8757 -2.2157 -0.6256 3.5245
> -0.86455 -0.49795
> 1 96 0.056782 0 0.081132 0 0 0.056782
> -0.056782 -0.045111
>
> The first two records (0 and 24) have a value which is about twice as
> much as the following (48, 72 and 96), which seem to be going towards a
> lower steady-state level.
>
> With SS=1 it does work as expected, but when I will add the compartments
> for the other drugs, SS=1 will interfere with those.
>
> I am sure I am misinterpreting something here, but in my understanding,
> it should not matter whether I choose SS=1 or SS=2, as long as the dose
> is the first one in the dataset... SS=1 forgets the past dosing history,
> while SS=2 remembers it, but what difference does it make if there was
> no other dose in the past?
>
> Thank you in advance to anyone who can help - or even just had the
> patience to read all this.. ;)
> Paolo
>
> --
> ------------------------------------------------
> Paolo Denti, PhD
> Post-Doctoral Fellow
> Division of Clinical Pharmacology
> Department of Medicine
> University of Cape Town
>
> K45 Old Main Building
> Groote Schuur Hospital
> Observatory, Cape Town
> 7925 South Africa
> phone: +27 21 404 7719
> fax: +27 21 448 1989
> email: paolo.denti
> ------------------------------------------------
>
--
  Alison Boeckmann
  alisonboeckmann
Received on Fri Oct 09 2009 - 15:10:06 EDT

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