From: Sabine Wittemer 
Subject: [NMusers] nonmem
Date: Mon, 22 Apr 2002 11:50:10 -0700
 
 Dear Sir,
 
 I'm a PhD student from Germany and I just start learning something about POPPk and Nonmem. As I was
looking at the internet about this topic I found your adress. As this is a very complex topic you maybe
can help me with the follwing question.
 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.
 
  Thank you for your cooparation
  Sabine Wittemer

*******

From: Lewis B Sheiner 
Subject: [NMusers] Re: nonmem
Date:  Mon, 22 Apr 2002 11:50:10 -0700

 nmusers, the NONMEM users group, may be able to help you ..

-- 
   _/  _/  _/_/ _/_/_/ _/_/_/  Lewis B Sheiner, MD (lewis@c255.ucsf.edu)
  _/  _/ _/    _/_    _/_/     Professor: Lab. Med., Bioph. Sci., Med.
 _/  _/ _/        _/ _/        Box 0626, UCSF, SF, CA, 94143-0626
 _/_/   _/_/ _/_/_/ _/         415-476-1965 (v), 415-476-2796 (fax
 
*******

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