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I am interested in understanding why adjustments to
(objective) measures of drug clearance are often
normalized (per kg, m2, 1.73m2, etc).
Given that the renal clearance of drugs can be
accuracy calculated by urinary recovery and systemic
exposures (AUC), yielding clearance values in volumes
per unit time, "normalization" appears to introduce
variability and potentially bias to results. This
seems to be greatest when evaluating the clearance of
drugs in pediatrics, where a similar net clearance can
be affected by 1 to 4-fold when clearance numbers are
divided by weights of 50 and 25 kg, respectively.
Alternatively, similar values for normalized clearance
in pediatrics and adults would appear to mask
differences in absolute (mL/min) clearance.
Review of the literature and classic PK indicates
widespread "normalization" of clearance (and volume)
values, without explanation for the biologic or
pharmacokinetic assumptions underlying these
Any input and discussion regarding these practices
with regards to CL(/F), CLrenal, Vd, especially
recommendations for reading materials, would be much
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First thing I suggest is to drop 'normalization' -- a better term is
'standardization'. I think of parameters like CL as having a value in
a standard individual e.g. weight 70kg, age 40 years, sex male,
creatinine clearance 6 L/h etc. This means that given a standard Cl
and a suitable model you can predict CL in a non-standard person from
wt, age, etc.
Allometric models for PK parameters such as clearance have a strong
theoretical and empirical basis. With a standard CL one can predict
the wider range of individual values across the human weight and age
range (from 28 weeks post conception onwards).
The process of deriving suitable models for say the relationship
between age and CL relies on individual estimates of CL. The model of
course may indeed introduce some bias because of model
misspecification but given a large enough number of individuals one
can make a reasonable attempt at describing the general pattern.
See Anderson BJ, Woolard G, Holford NHG. A model for size and age
changes in the pharmacokinetics of paracetamol in neonates, infants
and children. Br J Clin Pharmacol 2000;50:125-134. for an example.
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
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