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Background: Population analysis for patients and subjects revealed
best model for IV dosed drug (mg/kg basis) was a 2-compartment model.
Drug is cleared primarily by renal filtration, so as expected, Cl
related to renal function (Creat Cl). Structural model for
2-compartment model included Cl, Vc, V2 (peripheral) and Q
(intercompartmental clearance).
Question: There was no influence of covariates on Vc but there was a
significant body weight influence on both rate and extent of drug
distribution into the extravascular space. This was shown by
significant relationships between body weight and intercompartmental
clearance, Q, and body weight and volume of the peripheral compartment,
V2. Since dose was mg/kg, can someone offer explanation for the added
effect of body weight on these above two parameters. Thanks, Dave
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Was there a sex and body weight interaction also on Vc? What happens
when you normalize for body surface area?
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Hi David:
It is an interesting finding. I don't have the answer to your question
yet.
Can you please tell more about the significant relationships between
body
weight and V2 or Q you found, does it increase or decrease with body
weight?
I would recommend to use dose in mg rather than mg/kg in your pop PK
analysis. Using dose in mg/kg, you already have the V, CL, V2 and Q
parameters normalized by body weight.
Sam Liao, Ph.D.
PharMax Research
Blue Bell, PA 19422
215-6541151
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Dave,
I have seen this before. It might be due to the fact that your drug
should
not be dosed on basis of body weight. This exercise might try to
correct for
body weight-related differences in parameters that simply do not exist.
In
my example, mg/kg doses were applied to potentially correct for higher
volume of distribution and clearance at higher weight values, but as a
result for instance clearance was lower at high and higher at low body
weight, thus the model clearly overcorrected the parameters. The other
compartmental model parameters were similarly affected, but clearance
was
the most obvious one.
Not applying weight-normalisation resulted in individual clearance
estimates
evenly distributed around the population estimate over the entire range
of
weights. This to me pointed that weight-normalisation was not correct
for
this model and that dosing should have been done in mg rather than in
mg/kg.
Klaas
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Reply to David Benziger,
David, What about "more body weight = more fat" so if your compound is
lipophilic there is a bigger compartment for it to be dissolved I into
?
Andrew Sutton
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Sorry for the confusion
1. Pop PK analysis based on total dose
2.Both Q and V2 increase with increasing body weight.
Dave
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Hi Dave,
Clearance and volumen are just not strict proportional to body weight.
If
Q=THETA(1)*WT^THETA(2)
and V2=THETA(3)*WT^THETA(4), and either of THETA(2) or THETA(4) are <>
1, a
weight dependency remains after
normalization with WT^1.
Thomas
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Hello,
1. Your significance based testing (ie.purely statistical) results
depend on
the design of the trial. The range of body sizes, for instance, given
the
between-subject variability is important to consider.
2. Assuming dose-proportional PK, mg/kg should not influence parameter
estimates (compared to mg dosing) and their relationship to covariates.
3. My personal bias would be to place more faith in the valuable prior
(general literature on allometric scaling and developmental physiology)
information available on body-size and/or age related changes in CLs
and Vs.
I am in support of the earlier comment about reviewing the
physico-chemical
properties of the drug molecule, site of action and their influence on
PK
parameters. Again, you might also want to consider what you plan to do
with
the model developed.
Regards,
Joga Gobburu
Pharmacometrics,
OCPB, CDER, FDA
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)