Re: Unreasonable VSS estimate

From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: Unreasonable VSS estimate Date: Tue, 08 May 2001 08:02:21 +1200 The suggestions from Bill and Leonid seem to be focussing on a different question from the one that was asked. I personally prefer not to use the physiologically uninterpretable alpha, beta parameterization and the original question asked about VSS. The original question was based on the assumption that if a SHAM estimate of Vss was different from a NONMEM estimate then the NONMEM estimate was unreasonable. Estimation of VSS using SHAM requires an assumption about the input function i.e. the mean absorption time has to be assumed. How was this done for the oral data? SHAM methods typically assume homoscedasticity (additive residual error model). What residual error model was used with NONMEM? If a constant CV (proportional error model was used then more emphasis would be given to the later observations when using NONMEM and it is these values that critically influence the estimate of VSS. A mixed additive and proportional error model in NONMEM may be appropriate although there is not really much data to obtain precise estimates. Finally, and perhaps most importantly, what did the fits look like? Did you get good individual predictions? Did the typical value predicted curves scatter themselves more or less at random around the individual value predicted curves? If the predictions are good from NONMEM and the purpose of doing the modelling is to make concentration predictions in these rats then it really doesnt matter what the estimate of VSS happens to be. Nick -- Nick Holford, Divn Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556 http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm