From: "RIGBY-JONES Ann, Research Fellow" ann.rigby-jones@phnt.swest.nhs.uk
Subject: [NMusers] interoccasion variability
Date: Mon, 6 Feb 2006 12:46:22 -0000

Dear All

I'd be grateful for any opinions concerning the definition of an 'occasion' for the
purposes of estimating interoccasion variability.  In our study, critically ill
paediatric patients will receive a continuous variable rate i.v. infusion over
several days.  Blood samples (at least two) will be collected each day.  Is it
reasonable to treat each consecutive day as a different occasion? 

Many thanks

Ann

Dr Ann Rigby-Jones
Research Fellow, Anaesthesia Research Group, Peninsula Medical School

Department of Pharmacy
Level 5
Derriford Hospital
PLYMOUTH
Devon, UK
PL6 8DH

Tel: 44 (0) 1752 763414
Fax: 44 (0) 1752 763418
E-mail: ann.rigby-jones@pms.ac.uk

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From: "Serge Guzy" GUZY@xoma.com
Subject: RE: [NMusers] interoccasion variability
Date: Mon, 6 Feb 2006 09:48:28 -0800

That is not my understanding of inter-occasion variability.
When you study the same subject on, let say, two different occasions, it
is possible to get two different time profile not only due to the
measurement noise but also due to a change in the individual PK
parameters for that specific individual (sometime due to change in some
covariate with time).  Usually, you will take the first full time
Profile (let say starting day 1, finishing day 10) and will define it as
belonging to the first occasion and then the second trial (let say
starting day 30, finishing day 40) and will define it as belonging to
the second occasion. I do not think that it is appropriate to take one
trial data and associate each consecutive day as a different occasion.
Serge Guzy
President POP-PHARM

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From: "Mats Karlsson" 
Subject: RE: [NMusers] interoccasion variability
Date: Mon, 6 Feb 2006 20:52:14 +0100

Dear Ann and Serge,

It is true that interoccasion variability is introduced to handle parameter
variability within a subject over time. Thus the lower limit of what may
constitute an occasion is the interval necessary in order to obtain an
estimate of the parameter. Thus, every dosing interval may constitute an
occasion. For example for a parameter like bioavailability, this is often
the most reasonable definition. To allow separation between interoccasion
and residual variability it is necessary to have at least two observations
per occasion for at least some of the occasions.

Thus, regarding Ann's original question, I think it is reasonable to treat
each day as a separate occasion (at least is the half-life is below about 8
hours). However, I would be careful and inspect the result to make sure that
you are not treating what are systematic changes with a random effects
model. If some patient has deteriorating eliminating organ function over
time and some other patient on the other hand improves consistently over
time, interoccasion variability is not the right model (but it will lower
the OFV compared to a model with no time-variation).

Best regards,
Mats

--
Mats Karlsson, PhD
Professor of Pharmacometrics
Div. of Pharmacokinetics and Drug Therapy
Dept. of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
SE-751 24 Uppsala
Sweden
phone +46 18 471 4105
fax   +46 18 471 4003
mats.karlsson@farmbio.uu.se
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From: "SIMON Nicolas" nicolas.simon@mail.ap-hm.fr
Subject: RE: [NMusers] interoccasion variability
Date: Tue, 7 Feb 2006 10:18:59 +0100

What difference shall we make between IOC and inter-individual variability?

In my point of view, IOC belongs to the difference of an individual PK parameters
between i.e. monday and another day. Each PK profile is seen as a new occasion.

Intra-individual variability is more global and also takes into account that an
individual may have a PK parameter changing during one PK profile (i.e. due to
biological rythms). 

Best regards,
Nicolas SIMON


Department of Clinical Pharmacology
Medical School of Marseilles
27 Bd Jean Moulin
F-13385 Marseilles
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