Re: Pharmacokinetics, allometry and flat earth theories
From: Paul Hutson <prhutson@pharmacy.wisc.edu>
Subject: Re: Pharmacokinetics, allometry and flat earth theories
Date: Thu, 04 Oct 2001 09:55:57 -0500
At 02:33 PM 10/4/2001 +1200, Nick Holford wrote:
> Deliberately applying BSA to clearance and volume of distribution
in the
> face of these facts is comparable to believing the earth is flat.
I agree with Nick (nice review), and our fits of chemotherapy PK data
do
not support the use of BSA over other scaling (including the topotecan
data for which I inquired earlier this week). Ratain and others have
argued before against the willy-nilly use of BSA for scaling cytotoxic
treatment doses, but it has become almost a sacred cow in oncology.
Part
of the reason is likely that clinicians are not familiar with using
a
factor of ^0.75 in calculations: they are dosing using BSA slide rules,
nomograms, or four function calculators.
Since it is in oncology and pediatrics where this scaling is seen most
often, it is my opinion that the following should be addressed in reports
of investigative PK for new drugs:
1. Does a scaling factor of wt, wt^0.75, or BSA significantly improve
fit?
2. Is the improvement in minimization function significant wrt interpatient
variability. That is, is there a significant improvement in the ability
to
predict clearance (and resulting AUC) based upon increasingly complex
factors (eg, wt vs "ideal" or "lean" wt vs wt^0.75 vs BSA) compared
to the
remaining variability (ETAs, if you will).
3. If indeed the wt^0.75 or wt^x scaling is the most general in our
fits,
we need to report it as such, and not yield to manuscript reviewer's
arguments that it is awkward.
We may not be able to change the FDA-approved labeling of extant drugs
dosed by BSA, but we can promote the accurate representation of new
products.
Paul Hutson, Pharm.D.
Associate Professor (CHS)
UW School of Pharmacy
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