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RE: [FORGED] Phsysiological model

From: Andre Jackson <jacksonan1945>
Date: Tue, 6 Oct 2015 08:02:06 -0400


The K_Gutmet is a first order rate constant (1/h) for gut metabolism so it
is not predicted from Cl and Volume and you are correct it should have an
exponent of -1/4.


-----Original Message-----
From: owner-nmusers
Behalf Of Nick Holford
Sent: Tuesday, October 6, 2015 1:11 AM
To: nmusers
Subject: Re: [FORGED] [NMusers] Phsysiological model


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 - 08:02:06 EDT

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