RE: Rational of using IOV
Thanks to all for your comments, I didn't expect so much.
If the occasion correspond to a specific dose (i.e. 1st dose or later) then the question is, shall we expect a variability related to the duration of the treatment? In that case, we will have as many occasions as doses. The number of occasion can inflate rapidely and likely with few patients per occ. That doesn't sound good for me. Should we expect something like an overparameterization?
However, from a clinical point of view, a dose = an occasion, seems reasonable when the pathology may interfere with the PK (i.e. renal function and antibiotics for pyelonephritis, cancer and overall well being). If we combine observations coming from different doses or chemotherapy cures (in my example), I am not sure that it's relevant and even that could lead to false interpretation.
Best regards
Nicolas
----- Message de [email protected] ---------
Date : Tue, 2 Nov 2010 03:10:48 +0100
De : mats karlsson <[email protected]>
Répondre à : [email protected]
Objet : RE: [NMusers] Rational of using IOV
À : 'Stephen Duffull' < [email protected] >, 'Nick Holford' < [email protected] >, [email protected]
> Hi Steve,
>
> I think we can apply some mechanistic insight into IOV in most cases. For
> example for absorption parameters, it is difficult to see that anything but
> each dosing occasion would constitute a separate occasion. There may however
> be situations where it is difficult to judge properly and IOV may not be
> modeled ideally. Then however, not only IOV, but also IIV and RV become
> nuisance parameters as they will not represent the true IIV or RV.
>
> Best regards,
>
> Mats
>
> Mats Karlsson, PhD
>
> Professor of Pharmacometrics
>
> Dept of Pharmaceutical Biosciences
>
> Uppsala University
>
> Sweden
>
> Postal address: Box 591, 751 24 Uppsala, Sweden
>
> Phone +46 18 4714105
>
> Fax + 46 18 4714003
>
Quoted reply history
> From: [email protected] [mailto:[email protected]] On
> Behalf Of Stephen Duffull
> Sent: Monday, November 01, 2010 10:49 PM
> To: Nick Holford; [email protected]
> Subject: RE: [NMusers] Rational of using IOV
>
> Nick
>
> While I agree that BOV is not solely a nuisance parameter it is a design
> specific parameter and hence can be somewhat of a nuisance. By design
> specific we can formulate settings in which the design of the study changes
> the estimate of BOV.
>
> To estimate the variance between occasions the duration of the occasion
> needs to be defined (a priori). If the occasion is long then the estimate
> of BOV will tend to zero since the integral over the occasion to get the
> average parameter value will integrate over the random variability. If the
> occasion is short then it will tend to a larger positive number. Imagine an
> occasion of 1 hour versus 1 year. I realise that most tend to use a dose
> interval as an occasion but this is also arbitrary as is clinic visits. The
> duration of the occasion would need to be indexed to the substantive
> inferences of the model to ensure that any influence that BOV has can be
> assessed in terms of model predictions.
>
> Given that BOV is design specific then how should this be interpreted in any
> given circumstance? Note that being design specific doesnt preclude the
> benefit of BOV in its role as an estimable but nuisance parameter (i.e. to
> reduce bias in estimates of the population mean parameter values).
>
> Steve
>
> --
>
> Professor Stephen Duffull
>
> Chair of Clinical Pharmacy
>
> School of Pharmacy
>
> University of Otago
>
> PO Box 56 Dunedin
>
> New Zealand
>
> E: [email protected]
>
> P: +64 3 479 5044
>
> F: +64 3 479 7034
>
> W: http://pharmacy.otago.ac.nz/profiles/stephenduffull
>
> Design software: www.winpopt.com
>
> From: [email protected] [mailto:[email protected]] On
> Behalf Of Nick Holford
> Sent: Tuesday, 2 November 2010 8:33 a.m.
> To: [email protected]
> Subject: Re: [NMusers] Rational of using IOV
>
> Thierry,
>
> Between subject variability (BSV aka IIV) and within subject variability
> (WSV aka IOV) describe the limits of what we can identify as sources of
> variability.
>
> I don't consider this a nuisance -- it is an opportunity for learning. The
> random assumption used for estimation of WSV is a convenient way of
> describing the size of the problem. If we recognize there is a large element
> of WSV then it may stimulate thinking and further investigation to try and
> understand it.
>
> Ignoring WSV will give a false impression about what can be gained from TCI
> (aka TDM). TCI can only hope to remove the BSV part of unpredictable
> variability.
>
> See Holford NH. Target concentration intervention: beyond Y2K. Br J Clin
> Pharmacol. 1999;48(1):9-13.
>
> Best wishes,
>
> Nick
>
> On 2/11/2010 2:34 a.m., Buclin Thierry wrote:
>
> Dear James,
>
> I always thought that intra-individual variability (IIV) classically
> represented the immovable limit on the gains to be expected from TDM IOV
> being indeed used only in a minority of population PK analyses. Both intra-
> and inter-occasion variability actually represent nuisance. We agree on the
> point that specifying an IOV term in a model will decrease the residual IIV.
> But wouldnt this precisely give a falsely favorable impression about
> potential gains from a TDM program? Am I wrong to think so?
>
> Kind regards
>
> Thierry
>
> De : James G Wright [mailto:[email protected]]
> Envoyé : lundi, 1 novembre 2010 14:04
> À : Buclin Thierry
> Objet : Re: [NMusers] Rational of using IOV
>
> Dear Thierry,
>
> I hope you are well. I think you are right to highlight the importance of
> IOV for TDM, but I would argue it is very important to include it in the
> model. This is because IOV places an immovable limit on the gains from TDM.
> The classic error is to develop a TDM strategy mistakenly lumping IOV with
> IIV, and drastically over-estimating the utility of TDM.
>
> Best regards, James
>
> On 01/11/2010 11:55, Buclin Thierry wrote:
>
> Hi Nicolas
>
> My short answer would be another question: what is the aim of your analysis
> ?
>
> IOV is fine to split variability into inter-individual,
> intra-individual-inter-occasion and intra-individual-intra-occasion random
> components. This is excellent for data description, and can bring
> interesting insight into the mechanisms explaining variability. But if you
> want to use your results for prediction, e.g. to devise a TDM program, you
> wont be able to draw relevant information from IOV: a blood sample obtained
> in a patient on a certain occasion wont inform you on your patients
> behavior on another occasion; in this situation, a model merely
> distinguishing inter-individual and intra-individual variability components
> is easier to exploit. Thus, there may be good reasons not to use IOV even
> when it would be possible.
>
> Kind regards
>
> Thierry
>
> Thierry Buclin, MD, PD,
>
> Division of Clinical Pharmacology and Toxicology
>
> University Hospital of Lausanne (CHUV)
>
> Lausanne - SWITZERLAND
>
> tel +41 21 314 42 61
>
> fax +41 21 314 42 66
>
> On 1/11/2010 10:53 a.m., Nicolas SIMON wrote:
>
> Dear colleagues,
>
> could someone give me an advice about the rational of using IOV in a
> particular circumstance?
>
> We have data from a clin trial with 3 occasions for each patient. It was a
> chemotherapy and the patients have received up to 7 cures. The issue is that
> the 3 occasions differ from one patient to another.
>
> Patient X may have be seen on cure 3, 5 and 7 while patient X+1 was seen on
> cure 2, 5 and 6 or whatever...
>
> It seems to me that combining the 1st occ of all patients is meaningless (as
> for 2nd and 3rd).
> Shall we use as many occasions as cures (7 in our dataset)? In that case,
> how many patients by occ is relevant as a minimum? For certain occ we may
> have few patients. Combining cures is hazardous and has no clinical
> justification.
>
> Best regards
> Nicolas
>
> Pr Nicolas SIMON
> Universite de la Mediterranee (Aix-Marseille II)
>
> --
> James G Wright PhD,
> Scientist, Wright Dose Ltd
> Tel: UK (0)772 5636914
>
> --
> Nick Holford, Professor Clinical Pharmacology
> Dept Pharmacology & Clinical Pharmacology
> University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
> tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
> email: [email protected]
> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
----- Fin du message de [email protected] -----
--
Nicolas SIMON
Universite de la Mediterranee (Aix-Marseille II)
http://annuaire.univmed.fr/showuser.php?uid=simon.n