RE: Covariate Models Using Weight

From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com> Subject: RE: Covariate Models Using Weight Date: Wed, 17 Nov 1999 09:08:04 +0100 I totally agree with you, Nick, when you highlight the importance of "biology and mechanism when choosing a model". And I also agree with the value of allometry in general. But only in general. And only in the context of interspecies correlations. I don't believe in allometry when it is applied to a single species like humans. Specifically, the dependence of CL on body size is very complex and cannot be modelled in terms of a simple and universal function like CLi = CLstd * (Wi/Wstd)**3/4. First of all, we cannot apply the same function for drugs eliminated mainly via hepatic metabolism and via renal excretion controlled either by glomerular filtration, or by enzymes that govern active secretion and reabsorption, or both. Then, if a drug is extensively metabolised and the hepatic blood flow does not play any significant role (most typical case), the dependence of CL on body size is minor, and it is usually better correlated with LBM or IBW than with WT itself. Of course, TVCL=THETA(1)+THETA(2)*(WT-70) is not ideal, but most suitable as the first approximation. TVCL=THETA(1)*(WT/70)**THETA(2) might be preferable if the range of WT is wide enough, however, THETA(2) certainly should not be fixed to 0.75. The situation with V is not less complicated than with CL. Firstly, there is no V, but VC, VP, etc., and each volume may depend on body size differenly. Again, allometry is not something to be taken into account when building a model for one species. Best regards, Vladimir ---------------------------------------------------------------------- Vladimir Piotrovsky, Ph.D. Janssen Research Foundation Clinical Pharmacokinetics B-2340 Beerse Belgium Email: vpiotrov@janbe.jnj.com