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Re: [FORGED] Phsysiological model

From: Nick Holford <n.holford>
Date: Tue, 6 Oct 2015 18:11:06 +1300


Standardizing parameters with allometric models does not bring the
(minor) benefits that can be obtained by centering linear models. In
fact it is easy to prove that standardizing cannot change anything
except the scale of the parameter that is estimated. Thus you can use
any standard value and this will not change the quality of the fit in
any way.
See Anderson & Holford (2011) and slide 30 & 31 in

However, there are major advantages for humans who try to compare
results from different studies if a common standard is used. A common
standard for weight is 70 kg (Holford, Heo & Anderson 2013). The
practice of using the median weight to standardize allometric model
parameters is to be discouraged because each study will report a
different parameter even if the true parameter is the same simply
because the median weight varies from study to study.

Be careful using allometric theory with rate constants. I don't know
what K_Gutmet is supposed to describe but if it is a first order rate
constant that can be predicted from a clearance/volume then the
allometric theory exponent is -1/4 not 3/4 (0.75 as you have written).


1. Anderson BJ, Holford NHG. Tips and traps analyzing pediatric PK
data. Pediatric Anesthesia. 2011;21(3):222-37.
2. Holford N, Heo YA, Anderson B. A pharmacokinetic standard for
babies and adults. J Pharm Sci. 2013;102(9):2941-52.

On 6/10/2015 6:17 a.m., Andre Jackson wrote:
> All:
> I am attempting to take a Physiological model presented in the
> literature and place it into Nonmem with the help of the authors. A
> point was raised related to centering parameters which I would
> appreciate some feedback.
> In the published paper, model parameters such as Cardiac output are
> allometrically scaled as power models:
> QCO=15.87*(BW)**0.75
> and gut metabolism as:
> K_Gutmet=THETA(2)*(WT)**0.75)
> My question is should I use these equations as stated in the
> publication or should I center the estimates as e.g.,
> QCO=15.87*(WT/WTstd)**0.75
> The weights that will be investigated go from 30 kg up to 80 kg.
> It would also be very helpful if one can give me an explanation as to
> why or why not.
> Thanks
> Andre

Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730 mobile:NZ+64(21)46 23 53
email: n.holford

Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & Clinical Toxicology. 2014;2(2):1023-34.
Holford N. Clinical pharmacology = disease progression + drug action. Br J Clin Pharmacol. 2015;79(1):18-27.
Received on Tue Oct 06 2015 - 01:11:06 EDT

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