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A very nice review article just appeared in the European Journal of
Pharmaceutics and Biopharmaceutics 50 (2000)3-12 by Lobenberg and Amidon,
entitled " Modern bioavailability, bioequivalence and biopharmaceutics
classification system. New scientific approaches to international regulatory
standards". This article and the references should get you started on a quest
for Ka. You should be able to get a copy on the net at
http://www.elsevier.com/locate/ejphabio.
Art Straughn
UT Memephis
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About bioavailability:
Many software packages, among them the iterative Bayesian
(IT2B) and the NPEM population modeling software in the USC*PACK
collection, can determine both the absorptive rate constant and the
fraction of an oral dose absorbed, when the data is that of a single
study consisting of an intermixed IV and PO dosage regimen. One does
not have to do 2 separate studies - one IV and the other PO- and
compare the AUC's any more. Simply by giving a dosage regimen
consisting of some IV and some PO doses, one can determine both Ka,
the absorptive rate constant, and F, the fraction of an oral dose
absorbed, in a single study, in which there is much less chance of
parameter values changing than there is between 2 separate studies.
Respectfully,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.aaa.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
***
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Dr Jelliffe
I don't agree completely. You still need some good priors to get a
reliable estimate of F. Thus, I don't think that we can skip traditional
phase I study in which an iv dose is given along with an oral dose,
separeted by a sufficient washout period, especially for labelling. Once
this data is available, I agree that you can estimate bioavailibility, using
bayesian method or other pop PK method, even if both IV and Oral are not
given to the same subject.
I don't agree either that there is less chance of parameter values changing
just because the study is performed in the same study. A crossover study
offers the same advantage (i.e.,estimation of intra vs inter subject
variability).
Eric Masson,
Scientific Director
Anapharm Inc.
emasson.aaa.anapharm.com
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Dear Dr. Masson:
Thanks for your note. Try the software and then see. One
always likes "good priors", but that is not the point. The point is
that there is software by a number of people that can do the job of
estimating bioavailability from an intermixed regimen consisting of
both IV and PO doses. One point is that each subject should ideally
receive the doses by both routes.
I do not understand your statement that "Once this data
is available, I agree that you can estimate bioavailability, using
bayesian method or other pop PK method, even if both IV and Oral are
not given to the same subject". I do not know of any method to
estimate F when the subjects do not get the doses by both routes, as
you seem to state.
As to the issue of changing parameter values during the
study, there is always more opportunity for parameter values to
change when the study takes place over a longer period of time, when
there is first a study #1, a washout period, and then a study #2. A
randomized crossover study tends to protect against the statistical
effects of these random changes, but cannot prevent such changes from
taking place. The ability to compress 2 studies into one, with no
washout, using an intermixed PO and IV dosage regimen, is an
advantage here, and tends to minimize such random changes.
Sincerely,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.-a-.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)