Nick Holford wrote:
Non-proportionality (aka non-linearity) of metabolite formation from
parent is not really an issue. With the right design (i.e. suitable
doses of parent) then this can be discovered from just giving the
parent.
The key assumptions of metabolite models are about how the
Dear All,
I am analyzing a data set pooled from 4 clinical studies with rich
sampling. When I fit a 2 comp oral absorption model with lag time using
FO, I got successful minimization with COV step, but minimization was not
successful when I used FO parameter estimates as initial estimates for
Thank you all for the responses and it is very useful.
Regards,
Ayyappa Chaturvedula
GlaxoSmithKline
1500 Littleton Road,
Parsippany, NJ 07054
Ph:9738892200
__
Dear All,
I am analyzing a data set pooled from 4 clinical studies with rich
sampling. When I fit a 2 comp oral
As shown by X. Wang, FO, FOCE and LAPLACE form a hierarchy of approximations.
Both the FO and FOCE methods are based on the same underlying Laplacian
approximation to the
integral of the joint likelihood function of the random effects (eta's).
The basic Laplace approximation requires
Hi Bob,
I would just add one point of clarification. My understanding is that the
FOCE approximate is a Laplace-based approximation (related to it) only if
the within subject residual error model does not contain any
subject-specific random effects.
Wolfinger R (1993). Laplace's
James, Mahesh,
The F=1 fallacy has caused me no end of stress over the years, and
next time I may have to contend with the (almost irrefutable) argument
but Nick Holford said it was true.
As I never said this was a fallacy I dont think you need be stressed by
it. Everytime you use a model to
Dear Dr. Holford,
All I was suggesting was that once you have decided on which assumption you
like the most and start modeling the metabolite data then shouldn't
simultaneous modeling of the parent + metabolite be more preferable? The model
will take long run time any ways because it will be a
Ziad:
When FDA sends out a request, there should be a rationale for it. If it
is not clear enough, the sponsors should ask for clarification. If after
clarification, the sponsors felt the rationale is not scientific, then
the sponsors should not hesitate to appeal such requests. The sponsors
can
Hi Nick,
You have written many things that are true, however I think we are
differing on a very essential point.
Nick Holford wrote
Everytime you use a model to describe oral PK data alone you must
make an assumption about the dose that is absorbed.
You could make an assumption about this if
James,
I tried to deal with this in my previous reply. We do not differ. It is
fine for me if you make the assumption that you do not know Fm and you
estimate CLm/Fm and Vm/Fm. But this assumption in practice is an
assumption that Fm=1 when you actually are estimating the parameters.
There
Matt:
That's not true. Those two references are discussing when the linearized
structure model can also be derived from direct Laplacian approximation
of the marginal likelihood. When there is an interaction between
residual and between subject variability (or residual error model
contain
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