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Is it common in Pharma to conduct an IV PK study (or ADME 14-C) for a
drug that will only be used orally to get a handle on extent of
absorption and role of liver (bile) in excretion of absorbed
drug/metabolite(s)?
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Hi David,
Yes, if you want to know the oral bioavailability, you need to perform
IV-PK study.
Thanks
Dora
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There are a number of reasons why you would carry out an iv study for an
oral drug. Most of these would deal with preclinical studies and would
center around whether you need to know the absolute bioavailability of
the drug but you also might like to understand the relative influence of
clearance vs distribution in contributing to derived parameters such as
half-life. If these parameters are well characterized in preclinical
species and the clearance mechanisms and distribution are understood,
inferences can be drawn from Clinical human data.
Norman
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Though there are times when it is necessary to perform an IV study in
humans for a drug which is planned for oral administration only, there
should be a strong need. In the US a different route of administration
to humans requires a separate IND and separate toxicology studies. The
cost of this process is not small. Intravenous studies are generally
done with the preclinical species to determine the PK parameters. The
data from oral administration to humans and oral and intravenous
administration to animals are used to understand the pharmacokinetics of
the compound. If there is a question that can't be understood with that
data then a humans study with intravenous administration may be
necessary and will be planned. However, they are not done as a matter of
course.
Chris
Christopher Town, PhD
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Hello,
In response to" In the US a different route of administration
to humans requires a separate IND..."
A new IND is not needed for an intravenous formulation to test
bioequivalence. A CMC package does have to be submitted to the oral
IND; only short-term stability testing is usually needed as an Abs BA
trial is a "one- and-done" affair. Clinical supplies for future trials
are not needed. Non-clinical toxicity studies (also submitted to the
oral IND) are minimal if only a single dose/subject is planned.
The FDA guidances are available and informative.
Susan
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I assume you are not referring to human trials.
In order to completely characterize the safety profile of drug and
arrive at safe dose before advancing the molecule to phase I study, all
these studies needs to be done irrespective of intended route of
administration.
The studies are not limited to only those you listed, but lot more.
Regards,
Vinayak Nadiger
Vinayak Nadiger
Senior Scientist
Forma Therapeutics(Singapore)
11,Biopolis Way ,Helios # 08-05
Singapore 1386607
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Regarding iv studies for new drugs, I agree with Susan and Vinayak.
Only a CMC package or something similar but less that a full IND would
be needed in the US for a human iv study that supports another dosing
route to be marketed, and iv dosing to animals expected.
It's not unusual to do some kind of iv dosing study in humans, though
not strictly required, and best to negotiate/agree with the regulatory
authorities as to what you plan. You would not want to get an NDA hung
up because you failed to do a human iv study to determine absolute
bioavailability, if the regulatory authorities determine it is needed.
Tom
Thomas L. Tarnowski, Ph.D.
CACO Board / Organizing Committee
ttarnowski1.-at-.aol.com
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In (my) old days, the mid eighties, a triple cross-over of IV, low po
dose po and high(er) po dose in man was our standard; it gave quick
insight in bioavailability and variability, and a first glance at
dose-proportionality. And we did a 14-C study in man, because we needed
the radio-labeled excreta to identify the metabolites.
Nowadays, in my experience, IV in man is not commonly done for a drug
intended for oral use. 14-C studies in man are still done, even though
the FDA guidance is not specific; to the best of my knowledge there is
no absolute requirement to do such a study. However, the FDA does
sometimes ask for a 14-C study in man.
My best guess about whether or not they ask for it, is that it depends
on the outcome of the pre-clinical work.
If you have identified the larger part of the metabolites that you
expect in man (based on in-vitro work), and
you have very good and clear-cut results of tissue distribution studies
and a proper result of mass balance in a species that is metabolically
close to what you expect in man (based on in-vitro work) then it may not
be required.
frieda.ebes.-a-.incresearch.com | www.incresearch.com | INC Research(r)
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I have never done an iv 14 C study, but iv of non-labeled drug has been
used sometimes, and mostly in animal species for abs bioavailability
purpose
Kind regards
Lars
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If I may respond on this topic. It is relatively simply to conduct an
IV PK study with 14C-labelled drug if one takes advantage of the
ultrasensitive bioanalytical tool of accelerator mass spectrometry (AMS). In this
study design, an IV microtracer radiolabelled drug dose is administered
concomitantly with an oral pharmacological dose. This design requires
no additional IV animal toxicology or animal dosimetry. The design has
been set out in the most recent version of ICH M3, Exploratory Clinical
Studies together with the required toxicological support. I direct your
attention to the following papers;
1) Lappin G, Rowland M and Garner R C (2006) The use of isotopes in the
determination of absolute bioavailability of drugs in humans. Expert
Opin Drug Metab Toxicol, 2, 419-427.
2) Lappin G, Shishikura Y, Jochemsen R, Weaver R J, Gesson C, Houston B,
Oosterhuis B, Bjerrum O, Rowland M and Garner C (2010)
Pharmacokinetics of
fexofenadine: Evaluation of a microdose and assessment of absolute oral
bioavailability. Eur J Pharm Sci, 40, 125-131.
Reference 1) outlines why the simultaneous IV microdose together with an
oral pharmacological dose is the optimum study design since a) no IV /
oral cross-over study is required with its inherent variability b) the IV PK
are being determined in the presence of the therapeutic dose c) no
preclinical IV toxicology is needed d) IV formulation issues are vastly reduced as
just a few micrograms of labelled drug are needed and d) the study can be
piggy-backed onto an oral Phase I study.
I am happy to provide more information if needed.
Regards
Colin Garner
Professor Colin Garner BPharm PhD DSc FRCPath
Principal
Garner Consulting Services
Honorary Professor
Hull York Medical School
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