- On 11 Jan 2005 at 12:27:29, "vinu ca menon" (vinumenpharma.-a-.rediffmail.com) sent the message

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Dear All,

I am doing the Allometric scaling of an NCE. I am able to predict the

human parameters like Vd and CL with good Regression (0.9899 and 0.9587

respectively).

Whereas I could not predict the K01 with good regression by using Brain

Weight or other normal correction factors.

But when I used GFR as a correction factor my Regression and the slope

value has increased much(0.9587 and 1.008 respectively).

Could I use these correction factors which are totally related to

excretion to predict Absorption rate constant?

Thanks in advance,

Vinu,

DMPK. - On 11 Jan 2005 at 11:34:27, Tomas Martin (martin6.-at-.uiuc.edu) sent the message

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Dear Vinu:

with a slope value of 1.008, have you determined whether the 95%

confidence interval of the slope estimated value includes 1?

Take care.

Tomas. - On 12 Jan 2005 at 08:37:08, Nick Holford (n.holford.-at-.auckland.ac.nz) sent the message

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The following message was posted to: PharmPK

vinu ca menon wrote:

> Dear All,

>

> I am doing the Allometric scaling of an NCE. I am able to predict

the

> human parameters like Vd and CL with good Regression (0.9899 and

0.9587

> respectively).

> Whereas I could not predict the K01 with good regression by using

Brain

> Weight or other normal correction factors.

Vinu,

Allometric scaling of Vd and CL has good theory and experimental data

to support the theory i.e. allometric exponents of 3/4 on Cl and 1 on

Vd (see West et al. 1997,1999).

There is no theoretical reason to suppose that brain weight is related

to either of these whole body parameters except that brain weight is

related to total body weight and therefore will be indirectly

correlated via allometric theory. I consider the use of brain weight to

be an abnormal method rather than normal.

> But when I used GFR as a correction factor my Regression and the

slope

> value has increased much(0.9587 and 1.008 respectively).

> Could I use these correction factors which are totally related to

> excretion to predict Absorption rate constant?

The absorption rate constant is a complex parameter. From the simplest

perspective it can be thought of as a reflection of the gut

permeability constant. This would be expected to be independent of body

size and so there is little reason to use allometric relationships to

explain between subject variability. You may find empirical assocations

with other covariates such as GFR but you should be cautious about

accepting them if you do not have a good mechanistic/biological reason

to explain how they are helpful.

The benefit in terms of improving the predictability of concentration

profiles in other subjects is usually negligible when based on such

empirical 'discoveries'. From a practical perspective in humans the

main demographic covariates are weight and renal function (e.g. Mould

et al) followed by age (in the very young) (e.g. Anderson et al) and

then genetic polymorphisms (in no more than half the population -- by

definition).

I would also caution you against ever using the correlation coefficient

as a measure of goodness of fit. It is notoriously affected by outliers

and can give high correlations when it is obvious from looking at a

graph of the observed and predicted values that the fit is poor. You

should consider using the objective function (e.g. weighted sum of

squares, log likelihood) to guide model building and confirm your final

choice with some kind of predictive check (see Yano et al).

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

Mould DR, Holford NH, Schellens JH, Beijnen JH, Hutson PR, Rosing H, et

al. Population pharmacokinetic and adverse event analysis of topotecan

in patients with solid tumors. Clinical Pharmacology & Therapeutics.

2002;71(5):334-48.

Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NHG.

Acetaminophen developmental pharmacokinetics in premature neonates and

infants: a pooled population analysis. Anesthesiology

2002;96(6):1336-45

Yano Y, Beal SL, Sheiner LB. Evaluating pharmacokinetic/pharmacodynamic

models using the posterior predictive check. J Pharmacokinet

Pharmacodyn 2001;28(2):171-92

--

Nick Holford, Dept Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

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