Re: Covariate Models Using Weight

Date: Fri, 19 Nov 1999 12:01:50 +1300 From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: Covariate Models Using Weight James Wright wrote: > Just to make this clear - if I put on weight ie fat tissue, my clearance > increases? How? Does my liver get bigger? I do not expect an increase in weight due entirely to an increase in fat to increase clearance as predicted by the allometric model using weight. However, it is possible that there are extra metabolic demands put on the body by the extra fat that could lead to increased liver size and perhaps enhanced drug clearance. The allometric scaling model has to be underststood as a model for ONE covariate (weight) among many that might be associated with changes in clearance. Some of these covariates (age, obesity) will be correlated with weight so it will require some thought about a model and appropriate data with sufficient variability in the covariates to test the model. > I shall read your selected references... but given that only two > of them appear to be about clinical populations, I can hardly > consider this an overwhelming body of evidence. Would you like to offer some guidelines for what *you* consider "an overwhelming body of evidence". How much evidence does I have to provide to persuade you that an allometric exponent of 3/4 is reasonable when you provide no plausible counter evidence (see below)? May I suggest, you add to the evidence I wish you to consider the recent generalization of the theoretical basis for the 3/4 exponent model by West et al (1999)? > Can I suggest that you take a look at: > > Nawaratne S. Brien JE. Seeman E. Fabiny R. Zalcberg J. Cosolo W. Angus P. > Morgan DJ. > Relationships among liver and > kidney volumes, lean body mass and drug clearance. British Journal of > Clinical Pharmacology. 46(5):447-52, 1998 Nov I do not consider this small study of 21 healthy volunteers, with less than a 2 fold range in any of the covariates and more than a 4 fold range in clearance, relevant to testing the hypothesis about the 3/4 power model. I would like to refer you to Beuchat (1997) with an accompanying comment from Brown et al. which deals with the problems of considering empirical alternative exponents based on sparse data and the lack of any theory. I note that the authors of this study make the classical error of accepting the null hypothesis that LBM was not a predictor of anitipyrine clearance via a relationship to liver volume without any consideration of the power they had for detecting such a prediction. I would think the signal to noise ratio is just too small for this kind of study to offer any insights. Beuchat CA. Allometric scaling laws in biology [letter; comment]. Science 1997;278(5337):371; discussion 372-3. West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999;284(5420):1677-9. -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 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