Hi Diane,
With oral data only I would normally model with BLOCK(2) on CL/F and V/F or a DIAG(3) on CL/F, V/F and relative F. The latter may have some advantages for diagnostics, covariate model building etc. Also, if the underlying model truly is a mixture model on F, it could be parsimonious, needing mixture only one parameter only. You can't have IIV on CL, V and relF + off-diagonal elements without overparameterizing the model. However, although I have never tried it, I guess that a BLOCK(2) on CL and relative F could work, provided you have no ETA on V. If you also have an ETA on V all the problems you mention would be realized. I don't know if Nele has IIV on V, but if so, she should definitely reduce IIV model size. With respect to the mixture model, maybe it is possible to reparameterize such that the mixture component only concerns one ETA. Best regards, Mats Mats Karlsson, PhD Professor of Pharmacometrics Dept of Pharmaceutical Biosciences Uppsala University Box 591 751 24 Uppsala Sweden phone: +46 18 4714105 fax: +46 18 471 4003 From: Diane R Mould [mailto:drmo...@attglobal.net] Sent: Wednesday, April 15, 2009 6:16 PM To: 'Mats Karlsson'; nele.pl...@nycomed.com; nmusers@globomaxnm.com Subject: RE: [NMusers] OMEGA BLOCK with mixture model? Dear All I am not sure if this topic has been covered before or not, but as its related to the question below, I thought I would bring it up again. I have to wonder at the appropriateness of including the IIV term for F in an omega BLOCK structure in the first place? I can certainly understand estimating relative bioavailability and even estimating the associated variability for F, although there are often estimatability issues for an IIV term for F, even with IV data to help estimate F (or at least using a reference value for F like one formulation or one occasion). However because with orally administered drugs, CL is really CL/F then there is an inherent correlation between CL and F. With F and CL, this correlation is really in the THETA values so that if the model captures the correlation at the THETA level, ie allow for larger clearance with larger F (or vice versa), then the random effects for F and CL may be uncorrelated. However, if the population model does not capture that correlation at the THETA level, then correlation will be captured via the random effects, possibly resulting in an over-parameterized OMEGA matrix. As this latter situation seems to be very common (e.g. that the correlation between F and CL etc is picked up in the etas) then one might expect to see high condition numbers, zero gradients etc when IIV on F is added to the omega BLOCK structure. I would guess that as a rule, its probably more appropriate to keep the IIV term for F out of a BLOCK structure. Can anybody comment on this? Best regards, Diane _____ From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of Mats Karlsson Sent: Tuesday, April 14, 2009 2:08 PM To: nele.pl...@nycomed.com; nmusers@globomaxnm.com Subject: RE: [NMusers] OMEGA BLOCK with mixture model? Dear Nele, I think you may want to reconsider your model. If you have a negative correlation between CL and F1, it is likely to be related to high presystemic metabolism (first-pass) effect. If so, it seems strange to assume that the F1 distribution would not change between the two subpopulations. I think you need to have separate CL as well as F1 for the two subpopulations. Thus I would have CL and F1 described by ETA(1) and ETA(2) for subpopulation 1 and CL and F1 described by ETA(3) and ETA(4) for the second subpopulation. If hepatic elimination is responsible for the correlation, it is probably more parsimonious to use a semi-mechanistic model with a hepatic compartment (with a single ETA for variation in metabolic activity). Two examples of implementations of a separate hepatic compartment are : Piotrovskij et al. Pharm Res. 1997 Feb;14(2):230-7. Gordi et al., Br J Clin Pharmacol. 2005 Feb;59(2):189-98 Best regards, Mats Mats Karlsson, PhD Professor of Pharmacometrics Dept of Pharmaceutical Biosciences Uppsala University Box 591 751 24 Uppsala Sweden phone: +46 18 4714105 fax: +46 18 471 4003 From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of nele.pl...@nycomed.com Sent: Tuesday, April 14, 2009 5:09 PM To: nmusers@globomaxnm.com Subject: [NMusers] OMEGA BLOCK with mixture model? Dear all, I am trying to fit a PK model to oral data. In the data, we observed two things: First, CL seems to be negatively correlated with F1. Secondly, there seem to be two subpopulations in the exposure, let's say a large group with 'normal' and a second group with high exposure. I would like to identify the subpopulations using a mixture model, but keep the correlation between CL and F1. Now I ran into problems when coding the $OMEGA BLOCK. I figured the block to be something like: $OMEGA BLOCK(3) 0.1 ;CL1 0 FIX 0.1 ;CL2 0.01 0.01 0.1 ;F1 The error message that appears is: a covariance is zero, but the block is not a band matrix I assume that this means that I am not allowed to fix the correlation between the two clearance-omegas to zero. However, it would be unreasonable to allow a correlation, because the omegas belong to different subpopulations, so there can't be a correlation. On the other hand, I did not include subpopulations for F1, so how can I keep this correlation to both CL-subgroups? Any thoughts on this would be highly appreciated! Best wishes Nele ______________________________________________________________ Dr. Nele Plock Pharmacometrics -- Modeling and Simulation Nycomed GmbH Byk-Gulden-Str. 2 D-78467 Konstanz, Germany Fon: (+49) 7531 / 84 - 4759 Fax: (+49) 7531 / 84 - 94759 mailto: nele.pl...@nycomed.com http://www.nycomed.com County Court: Freiburg, Commercial Register HRB 701257 Chairman Supervisory Board: Charles Depasse Management Board: Dr. Barthold Piening, Gilbert Rademacher, Dr. Anders Ullman ---------------------------------------------------------------------- Proprietary or confidential information belonging to Nycomed Group may be contained in this message. If you are not the addressee indicated in this message, please do not copy or deliver this message to anyone. In such case, please destroy this message and notify the sender by reply e-mail. Please advise the sender immediately if you or your employer do not consent to Internet e-mail for messages of this kind. 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