RE: BOV
From: "Nick Holford" n.holford@auckland.ac.nz
Subject: RE: [NMusers] BOV
Date: Tue, September 21, 2004 3:47 pm
Ken,
I don't agree with your assertion that the model would necessarily be
overparameterized if one estimated a different BOV for each occasion. The way I
interpret Pravin's formulae for occasion specific '%CV of Pi' is that it computes
the occasion specific total variability estimated by averaging across all subjects
for any given occasion. The replication of each occasion comes from having several
subjects for each occasion.
Consider this 'thought experiment': A constant rate infusion of a drug is given to a
group of subjects. Concentrations are measured on each occasion at a time when
steady state for that occasion can be assumed. Clearance (CLi,n) is readily
calculated on each occasion (n) for each subject (i) from the infusion rate and the
measured Css.
Assume there is no systematic change in clearance from occasion to occasion. For
simplicity let us also assume that CL is normally distributed between and within
subjects. We can estimate the mean subject specific clearance by averaging the CLi,n
estimates over all occasions for each subject (CLAVGi). The SD of all the estimates
of CLAVGi is BSV. Now we calculate the SD of all CLi,n estimates on a specific
occasion -- call this PPVn for occasion n. It is the sum of the between subject and
occasion specific (within subject) variability. This corresponds to the '%CV of Pi'
defined by Pravin if one ignores the '%' and '*100'.
The occasion specific BOVn can now be calculated from SQRT(PPVn^2 - BSV^2). Thus I
would conclude it is possible to estimate BOV separately for each occasion given an
adequate design for estimation of the parameter in each subject on each occasion.
The BLOCK(x) SAME construction is a helpful NONMEM option when one wishes to assume
that BOV is the same for all occasions. It is not a requirement that one use this
when estimating BOV. Indeed one might consider that it should be a SOP to explicitly
test if the SAME assumption is supported by the data when estimating BOV.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/