Re: Re: nonmem

From: Nick Holford Subject:Re: [NMusers] Re: nonmem Date: Wed, 24 Apr 2002 04:53:31 +1200 Sabine, > Sabine Wittemer wrote: > > What is the impact of two different ways (linear vs. power) that are used to evaluate the effect of weight on clearance with respect to change in the objective function, diagnostic plots and parameter estimation. > > It would be very kind if you answer this question or give some advise for suitable literature. There are two aspects to your question. First of all what kinds of models might be used to describe between subject differences in clearance using weight as a covariate. Second, what criteria might be used to evalute the goodness of fit of the models. Models for the relationship between weight and clearance can be categorized as empirical or theoretical. A linear (slope plus intercept) function of weight is empirical and mechanistically unrealistic if the intercept is non-zero. Allometric models use a power function of 3/4 and are firmly based in both theory and experiment (see West & Brown 1997,1999, Holford 1996). I personally cannot see the point of attempting to use other models for weight and clearance. I suggest that you use the allometric 3/4 power model as the base model and then explore other covariates to see if they have additional explanatory information given the firm basis of an allometric relationship to weight e.g. see Anderson et al. 2000 [age], Gillooly et al. 2001 [temperature]. The goodess of fit of covariate models is based on the usual criteria of a good overall fit to the data based on graphs of observations and predictions. Covariate models can be evaluated on statistical and clinical grounds. Statistical criteria might be based on the probability of seeing a given improvement in objective function e.g. with an allometric model compared with the null (no weight in the model). Clinical criteria might be based on the magnitude of the change in clearance given the range of covariate values in the target population and the resultant predicted difference in effectiveness or risk of adverse effects. Reduction in the magnitude of between subject variability in clearance is another criterion that may be evaluated based on its impact on labelled dosing recommendations. Nick West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science 1997;276:122-26. West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999;284(5420):1677-9. Holford NHG. A size standard for pharmacokinetics. Clinical Pharmacokinetics 1996;30:329-332. Gillooly JF, Brown JH, West GB, Savage VM, Charnov EL. Effects of Size and Temperature on Metabolic Rate. Science 2001;293:2248-2251. Anderson BJ, Woolard G, Holford NHG. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children. Br J Clin Pharmacol 2000;50:125-134 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