interoccasion variability

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

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

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

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 _______________________________________________________