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The following message was posted to: PharmPK
I am currently working with pediatric nephrology to evaluate the
pharmacokinetics of various drugs in nephrotic patients with alterations
in serum albumin. I am evaluating data to enable a prediction of AUC
based on relevant clinical (and maybe demographical) characteristics.
For the highly protein bound drug: When I dose and weight normalize the
measured AUCs, age appears to be positively related and when I dose and
BSA normalize the measured AUCs, age appears to be negatively related.
Significant correlations do not appear to be an issue. The actual drugs
were based on BSA dosing for pediatrics. Any ideas?
One addition question: The AUC (zero to infinity) for single dosing and
AUC (zero to tau) for steady state are similar and the clinical
parameters at the two time points differ. My multiple regression
equations (for AUC) both contain albumin, but the two differ for the
second parameter (one uses GFR - single dose, and the other uses age -
steady state). I presume that I should use the one for steady state,
but I think we may have underdosed patients and hence their clinical
parameters look worse at steady state than single dose (subsequently
effecting Cl/F and AUC)- any suggestions?
Melanie S. Joy, Pharm.D., FCCP
Associate Professor
UNC School of Medicine
Division of Nephrology and Hypertension
UNC Kidney Center
CB #7155, 7005 Burnett Womack Building
Chapel Hill, NC 27599-7155
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The following message was posted to: PharmPK
Melanie,
The issue of how to deal with changes in body size and maturity in PK
is discussed in this review:
Anderson BJ, Holford NH. Mechanism-Based Concepts of Size and Maturity
in Pharmacokinetics. Annu Rev Pharmacol Toxicol 2007 (Oct 3 epub).
Its not clear what you mean by dose normalized AUC but in PK the
standard thing is to compute clearance from Dose/AUC. Clearance is the
fundamental parameter describing drug elimination.
I assume you mean by 'weight normalizing' that you expressed the
clearance (CL/F=dose/AUC) per kg of body weight. This is not a
biologically sensible method. BSA normalising ie. clearance/M^2 is
better but allometric scaling has the best experimental and
theoretical support.
You say the AUC from a single dose and the AUC at steady state are
similar. I interpret this to mean there is no treatment or time
associated change in clearance (on average). This seems to rule out
your speculation that treatment may have changed CL/F. "we may have
underdosed patients and hence their clinical parameters look worse at
steady state than single dose subsequently affecting Cl/F and AUC)".
I suspect the differences you are finding in explanatory factors for
Day 1 and steady state CL/F may be related to not fitting all the
values to a single model. Doing this naively by not recognizing that
the Day 1 and SS values come from the same patient is problematic.
A better analysis method would be to fit all the individual pairs of
CL/F on day 1 and at steady state to a model which tries to explain
how they are related to weight, age, treatment etc. Using a program
e.g. NONMEM that recognizes that the individual CL/F values come from
a single patient and that there are between patient variations is
important to properly model the covariate effects.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.aaa.auckland.ac.nz
www.health.auckland.ac.nz/pharmacology/staff/nholford
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