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Dear all,
Should the time points selected in calculating absolute
bioavailability by oral and intravenous administration be same or not?
My doubt is with different time points in oral and IV profile AUC will
definitley change, soas the absolute bioaavailability. Are there any
guidelines for my query.
Kindly clarify my doubt. Thanks in advance.
With regards,
Veeravalli Vijaya Bhaskar,
Aurigene Discovery Technologies Ltd
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If you are comparing an experimental drug with a comparator drug- make
sure you use the same time points collected. Sounds silly doesn't it
but???
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Hi Ed
what if one is comparing an oral formulation with iv? The initial
sampling times for an i.v. bolus would be pretty early (unless it is
an infusion) and rapid compared to oral administration. Moreover, the
drug may not be absorbed or be detectable when given by oral
administration. Wouldn't that be a waste of a sampling time point(s).
Just a thought.
manish
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Can someone clarify for me what may be a very naive question: what is
meant by "bioavailability by intravenous administration"?
If bioavailability refers to tissue concentrations, how is that
measured?
If bioavailability refers to the fraction that is absorbed following
an oral dose, how does that relate?
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Can you give idea about the selection of time points with the molecule
name
Regards,
K.Srinivas Rao
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Hi Vijay Bhaskar and all,
I do not see a real need for sampling at same time points/intervals
for Oral and IV..... i would probably do this when I compare with a
comparator in same route of administration...
IMHO, Initial (esp for Intravenous) and terminal phase sampling
intervals are important/crucial for AUC calculations (of course, all
the time intervals are important)....so i would be more concerned
about these time intervals than same time points....
Regards,
Martin Johnson
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Bioavailability is not 100% by iv administration if there is first
pass via the lung.
Wilkinson discussed this in a review many years ago. Most persons
forget this fact when considering drug distribution in the body.
For rigorous (compulsive) investigators, true 100% bioavailability
is only demonstrated by intra-arterial administration. Most Ethics
Committees would have trouble with that suggestion. We have done it,
but
only in the OR with a crash cart beside the volunteer.
Dan Sitar
Dr. Daniel S. Sitar
Editor in Chief, Journal of Clinical Pharmacology
Professor, Dept. of Pharmacology and Therapeutics
Professor, Dept of Internal Medicine (Clinical Pharmacology)
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Dear Prof Wolf,
When bioavailability is intended to refer to the site of action, some
investigators have monitored the effect, and taken the ratio of AUECs in
lieu of AUC for say a test and reference formulation, and termed it
pharmacodynamic bioavailability (or something similar).
Bioavailability of IV administration can also refer to a test of some
longer
acting IV formulations, where the drug elimination rate is slower (due
to
slower drug availability from the formulation).
Cheers,
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Tallahassee, FL 32307
shawn.spencer.aaa.famu.edu
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Hello,
I don't think your different sampling time point could give variable
AUC's unless your sampling frequency is too long (12/24 h) which is
usually at last sampling point in our routine preclinical pK. As IV
doesn't involve absorption we tend to take an early time point. In
case of PO you don't need to do that unless you wanna calculate
absorption rate constant.
However, If you have faced this kind of problem please post us some
data.
Thanks
Ravi Talluri
Sai Advantium
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Hello,
It makes sense if both the experimental and comparator drug are in the
same galenic form - that is tablet vs. tablet - as would be the case
of bioequivalence for oral administration.
Edmond
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Dear
The bioavailability is the fraction of unchanged drug that reaches to
the general circulation and in case of IV route it is 100%. In tissue
it s related to the distribution of drug that depends on many factors
like lipopjhiisity of drug, tissue affinity etc. Once drug reaches to
general circulation then it equilibrate in various tissue in case of
IV ad PO if dose is same then the difference of concentration of drug
in blood will vary.
Dr Zafar
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Dear Vijay
Q1. Should the time points selected in calculating absolute
bioavailability by oral and intravenous administration be same or not?
Not necessary. Because there is no absorption phase with IV route and
hence you should have early time points .
I addition plasma samples usually collected for less duration
compared to oral route where you one can collect for long duration.
..
Q2.My doubt is with different time points in oral and IV profile AUC
will definitley change, so as the absolute bioaavailability.
I think no impact on bioavailability but i am not sure.
Thank you
Rajasekhar Jaladi
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Dear All,
I agree with other group members that taking same time points for po
and iv routes is not a must for determining bioavailability. We should
select the time points such that we can sufficiently cover all the
phases i.e. absorption, distribution and elimination phases.
Another question which arises, s the use of dose normalized AUCinf vs
use of AUClast for calculating bioavailability.
Generally, if the difference between AUClast and AUCinf is less than
20%, then we use AUCinf otherwise use AUClast for bioavailability
determination.
In cases, where terminal phase is not well defined, we manually select
the terminal points for determination of elimination rate constants.
This manual selection can lead to bias and may not be acceptable to
the regulatory agencies.
Comments from experts are invited.
Best
Tausif Ahmed, Ph.D.
Principal Scientist
Sai Advantium, Pune, India
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Dear vijay,
I feel, we should think about PK study design and not worry about
matching time-points for IV and PO.
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Dear all,
Thanks a lot for suggestions. If a compound administered
by oral route has its Cmax in the first time point that was sampled
then how to go about it. IV generally we collect first sample at 5
min, whereas oral at 15 min. but if the compound that I had dosed by
oral route has its Cmax in the initial time point (i.e at 15 min),
then doesnt it make a difference in AUC and bioavailability if i
collect one more sample at 5 min.
Thanks & regards,
Veeravalli Vijaya Bhaskar
Aurigene Discovery Technologies Ltd.
[Sounds like you need some earlier times points after oral
administration. How do you know it is Cmax - db]
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Dear Veeravalli,
The chances of any observation being at Cmax are infinitesimally small.
Although it is an all-too-common practice to use the highest observed
concentration as Cmax, it is inevitably wrong. A good model of the
data will
give you a better estimate of Cmax, and often the Cmax is considerably
higher than the highest observation. The AUC for the model curve
(assuming
an appropriate model) will also be more accurate than AUC calculated
with
simple trapezoidal rule areas based on the data points.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Dear Veeravalli:
Like Walt pointed out, it is very difficult to accurately measure t
max and C max. For the programs I worked on that have very fast tmax,
I added a 7 min time point to better define/ estimate t max and c max
(for profiling and model fitting purpose). Adding a 7 min time point
changed CT profile from time 0 to 15 min and/or Cmax value for some of
the animals compared to the sampling scheme without it.
Regarding AUC, AUC = conc * time. The delta t between 7 min and 15
min is small (8 min) in the 24 hr sampling scheme, so the delta
AUC0-24 should not be significant in most cases. For the compounds I
worked with, the difference in AUC with and without the 7 min time
point is relatively small compared to the total AUC and the difference
in AUC did not change the F significantly or meaningfully.
Hope my experience help.
TK Chen, Ph.D.
Director, DMPK
Cylene Pharmaceutical
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