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

From: Paolo Denti <paolo.denti>
Date: Mon, 05 Oct 2009 09:37:05 +0200

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
------------------------------------------------


Received on Mon Oct 05 2009 - 03:37:05 EDT

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