RE: covariates

From: "Nick Holford" n.holford@auckland.ac.nz Subject: RE: [NMusers] covariates Date: Fri, September 17, 2004 7:51 pm Leonid, Thanks for making it clear that we agree that allometric scaling is a plausible model. It seems we disagree on whether or not one can assume that CL, V1, Q, V2 parameters of the two compartment disposition model are correlated with physiological/anatomical properties. I accept that it is an assumption that I make when I use allometric models to scale these parameters. Given my understanding of the physiological/anatomical processes that I expect to govern pharmacokinetic disposition I do not see any need to seriously question this assumption. I agree that common sense should be used to guide a covariate search - in particular biological/mechanistically guided common sense. I accept that one might use OFV changes as a screening procedure but of course not for formal hypothesis testing given the well known failure of the chi-square assumption for the null OFV change distribution using NONMEM. I do not consider covariate effects are of practical importance unless one can also show that the random effect variance (e.g. as estimated by OMEGA) for a parameter of interest (e.g. clearance) is reduced by some relevant amount. It is not uncommon to see drops in OFV suggesting covariate effects but with a negligible change in OMEGA e.g. See Matthews et al. for an example where the contribution of several covariates in explaining the variability in clearance was estimated and the predictive performance of each covariate model was tested. There are examples where the OFV fell but there was no improvement in clearance variance nor improvemement in predictive performance. Matthews I, Kirkpatrick C, Holford NHG. Quantitative justification for target concentration intervention - Parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides. British Journal of Clinical Pharmacology 2004;58(1):8-19 Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/