Re: Covariate Models Using Weight

Date: Thu, 18 Nov 1999 22:55:39 +1300 From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: Covariate Models Using Weight James Wright wrote: > I too agree that using prior information is essential in building a > sensible model but I draw the line at extrapolating from points on a > log-log plot representing different species to a clinical population of > patients. Please read Anderson et al. (1997) for data using human clinical populations. > Do we really believe that a human beings clearance changes in a > predictable manner if they put on a few kilos? If it is a matter of *belief* then YES I do believe that between subject differences in weight (even by a few kilos) are reflected in the typical individual by an increase in clearance. If I did not believe that then how would I explain in any meaningful biological way the extensive within and across species data showing that clearance and weight are correlated? > At least half of the western world is overweight these days. ... > Comparisons using children and adults are necessarily confounded ... Body composition and stage of maturation are separate covariates that can be helpful in describing between subject variability in clearance. These factors are correlated with weight and therefore a systematic approach to separating them can be based initially on the use of an allometric model using weight (Holford 1996). > I think in this day and > age we should be looking for useful predictive covariates rather than > claiming we can apply WT^3/4 to all possible drugs and patient populations > on very limited evidence. I am perfectly willing to listen to your suggestions for how to disentangle the separate influences of weight, body composition and maturation. My proposal is firstly to account for the influence of size using allometric scaling (perhaps using lean body weight instead of total body weight for obese patients), then introduce other covariates such as body mass index and age. How would *you* suggest it be done "in this day and age"? The allometric scaling exponent of 3/4 for functional properties (e.g. metabolic rate) and 1 for structural properties (e.g. blood volume) is based on extensive evidence (see Peters 1983 for a book on the subject and West et al. 1997 Table 1). I *believe* it is reasonable to extend the principle that if an exponent of 3/4 is reasonable for metabolic rate then it should also work for clearance, similarly an exponent of 1 for blood volume is reasonable for apparent volume of distribution. Of course, it has not been evaluated for "all possible drugs and patient populations". That would be absurd. But the model does have a theoretical and biological basis (West et al. 1997). It is not a black box empirical model. If a drug is eliminated renally then I feel comfortable using a marker of renal function e.g. predicted creatinine clearance, as a covariate for the renal component of drug clearance. This is the basic application of biology to modelling. The allometric relationship is being applied in the same way. Anderson BJ, McKee D, Holford NHG. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin. Pharmacokin. 1997;33:313-327 Holford NHG. A size standard for pharmacokinetics. Clin. Pharmacokin. 1996; 30:329-332 Peters RH. The ecological implications of body size. Cambridge University Press. 1983 West GB. Brown JH. Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997; 276:122-6 -- 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