Re: Parameterization!!!

From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: Parameterization!!! Date: Thu, 10 May 2001 22:25:53 +1200 Jean-Xavier, You wrote: > Indeed, if you think in term of interindividual variability, it seems > better to reparameterize your model with more physiologic parameters such > as volume and clearance, and then use an error structure (the ETAs) > directed to these parameters. I fully agree. > However, 1) models are just a pale description of reality, I fully agree. > and 2) it is important to remember that the TRANS > utilities (other than TRANS1) transform CL AND V back into rate constants ! Here we disagree. It is quite irrelevant what TRAN is used or what ADVAN or even if one uses $PRED which does not use any ADVAN or TRAN. The key issue about parameterization for population models is which parameters have random effects attached to them (as you say above) NOT the code that is used with those parameters to compute the model prediction. > Linear models (which are approximations of Michaelis-Menten kinetics and > diffusion processes) are built with rate constant, not clearance. Wrong again. The following is a linear model and perfectly legal mixed effects model for use in NONMEM. Look! No rate constant! $PRED CL=THETA(1)*EXP(ETA(1)) V=THETA(2)*EXP(ETA(2)) Y=DOSE/V*EXP(-CL/V*TIME) + ERR(1) > I think > that it might be dangerous to always use your principles when doing > resampling, especially when one bootstraps the errors, not the data. Would you like to be more specific about the dangers? And define what kind of bootstrap (parametric? non-parametric?) you have in mind? And why would the model parameterization make any difference for any kind of bootstrap? > If you prefer to reparameterize your models to CL and Vss, why do not use > the "non compartmental" approach which is based on the same principles of > linearity ? I leave SHAM analysis methods to those who are not really interested in pharmacokinetic analysis. Non-linear pharmacokinetic models are much more fun. Its a shame so many drugs are so potent and do not stress elimination pathways. We need more drugs like ethanol to make pharmacokinetics interesting. 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