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Dear Group members,
I have a simple query, if we have the human Pharmacokinetic data from
an Immediate Release (IR) product only and now want to design a
Bioequivalence study for a Modified Release (MR) formulation of the
same product, then how we will decide the time points for blood
collection in humans. We don't have any information on the
Pharmacokinetics of the MR product in humans.
Views from the experts are welcomed.
With Regards
Tausif Ahmed, Ph.D.
Metabolism and Pharmacokinetics Department
Ranbaxy Research Lab., India
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Hi Tausif,
In the case, if there is no innovator for the MR product and as you
say " no PK information in human is known for the MR product", the PK
time points for a clinical PK study will be guided by :
- the in-vitro release characteristics (of MR) and the
supporting formulation studies done in fluids/ media
simulating gastric fluid / intestinal fluid etc.
- The studies would be essentially comparative bio-
availability studies (rather than bio-equivalence) and first
study should be designed as a pilot study to understand the
variability (now due to the drug and the formulation). The
next study could be a more definitive / powered study with
information on PK and Variability obtained from the pilot study.
Hope this helps.
Regards,
Pankaj.
--
Pankaj Goyal, M.D.
Note: The views expressed are personal views of the sender.
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Dear Dr. Tausif,
First compare the release pattern and other in vitro data of MR
product with IR product. Based on the data, you can run a pilot
study in humans to characterize the PK profile of MR product. With
pilot data, you can fine tune the sample time points for MR product.
Hope I have answered your question.
Regards,
D Mallikarjuna Rao
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The following message was posted to: PharmPK
If your IR data are such that there is significant absorption in
colon, then
GastroPlus(tm) can be used to fit an appropriate absorption model.
However,
if the IR dose was all absorbed in the small intestine, then you
won't be
able to determine colon permeability from direct observation.
Instead, the
use of Caco-2 permeability along with the pKa(s) of the drug can help
provide an exst of colon permeability, and hence absorption in the later
hours for the MR formulation. Alternatively, ADMET Predictor(tm) can
be used
to predict Peff in jejunum and appropriate adjustments for colon can be
estimated automatically in GastroPlus.
Knowing the pharmacokinetics for the drug from iv data, or fitted from
enough IR data, will also be important.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
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The following message was posted to: PharmPK
Dear all,
For Bioequivalence study for a Modified Release (MR)
formulation of a product with only the human
Pharmacokinetic data from an Immediate Release (IR)
product.
For example - Let us consider, If product Tmax is 2
hrs
for Immediate Release (IR) product, Since our product
is an MR, we expect this product to be absorbed after
in intestine, hence we have to add gastric emptying
time to Tmax of Immediate Release (IR) product.
ie., 2 hrs + 2-3 hrs (gastric emptying time) = 4-5
hrs, hence we should have more sampling points more
after 4 hrs post dose.
This is my opinion,Dear all pls give your comments
regarding same.
Regards,
Dr.Sridhar
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Dear Tausif,
A bioequivalence study between an MR formulation and an IR formulation
is inappropriate, since, by definition., they will have different plasma
concentration-time profiles. If this is a novel MR formulation, then you
should design a small pilot study to evaluate the PK of the MR
formulation with reference to the IR. The sampling time-points for the
MR will initially be estimates, though if you know anything about the
dissolution/absorption rate data for the MR compared to IR, you may be
able to simulate a likely profile. Once you have some data on the MR
formulation, then you will be in a better position to fine-tune the
sampling schedule for future studies.
Regards,
David
Senior Director, Clijnical Pharmacology and Pharmacokinetics,
Shire Pharmaceuticals Group PLC
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A plea for defining abbreviations
IR Infra-Red??
MR Magnetic Resonance??
--
Professor Walter Wolf, Ph.D. Distinguished Professor of
Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California 1985 Zonal Ave., Los Angeles, CA
90089-9121
E-Mail: wwolfw.at.usc.edu
Telephone: 323-442-1405
Fax: 323-442-9804
PLEASE NOTE NEW WEBSITE
http://www.usc.edu/research/initiatives/bisi/
http://www.usc.edu/schools/pharmacy/faculty_directory/detail.php?id=59
[I think I worked these out but there have been a few recently that I
wasn't sure about. Thanks Walter - db]
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The following message was posted to: PharmPK
Tausif
You should try a series of discriminatory dissolution tests (not
necessarily by the pharmacopoeia monograph) trying to anticipate the
in vivo absorption kinetics. You may start reading the extensive work
on this by Prof. J. Dressman and stem from there according to your
needs.
Luis
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Dear Dr. Tausif,
While selecting time points for MR product, one should consider the
following points:
1. Compare the in vitro release pattern and other in vitro data of
the MR product with IR product.
2. The rationale for developing the MR product (e.g. one could
consider MR product for extending the duration of action, making once
daily formulation or safety considerations)
3. Run a pilot study of the MR product in comparison with IR product.
4. Fine tune the sample time points after reviewing the pilot study
data.
Hope, this will help you for designing the study.
Regards,
D Mallikarjuna Rao
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Hi,
It can be decided with in-vitro data and a pilot
study.
Regards,
Dr.Sridhar
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Dear Tausif,
Since you have the human Pharmacokinetics data of IR formulation, all
you need to do is comparative evaluation of rate and extent of In-
vitro release characteristics of Modified Release (MR) formulation
against Immediate release (IR) formulation in different dissolution
media like simulated gastric fluid or intestinal fluids (Which ever
applicable) at several pH conditions based on its site of absorption
of the drug in GI tract.
Testing conditions should be based on physicochemical properties of
the drug substance and the environmental conditions, the dosage form
might be exposed to after oral administration.
Based on the In-vitro release data calculate blood sampling time
points and first conduct a relative bioavailability study against
your IR formulation in a small size population to get PK profile of
MR formulation and develop relevant correlation for validation of
your BE study.
Corrections if any, are appreciated.
Regards
Shravan Kumar.Eduru.
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Dear Shravan,
You have addressed one important factor - dissolution/release. But
that is
not enough.
Unfortunately, some drugs have little or no absorption in colon, so
unless
the MR dosage form is a gastric retention system, it will typically
be in
the colon within about 4 hours, and after that, permeability in colon as
well as solubility/dissolution will govern what happens. Some drugs
exhibit
higher permeability in colon than in small intestine, some much lower.
Finding the permeability in colon is generally not trivial. The
PharmaProfiles radio capsule is one of the better methods I can think
of.
One might suspect that since Caco-2 cells are colon cells (although
cancerous), they might provide an indication of permeability in
colon. (I'm
still amazed that we use colon cells to estimate jejunal Peff,
considering
how different the morphology is between colon cancer cells and healthy
epithelium in the jejunum.)
If the IR data involved a dose that was absorbed over more than 3-4
hours,
then there may be sufficient data to estimate colon permeability from
those
data. If not, then some way to measure/estimate caecum and colon
permeability will be needed.
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
While I can see why David says that it is not appropriate to conduct
a BE
study between a MR and and IR formulation, I think it could be very
useful
to know how the bio-availabilities compare especially when the
formulation
is really novel and PD is proportional to systemic availability.
--
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
Tel: +44 (0)1483 455375. Direct: 688303
Mobile +44 (0) 7770 820 145 (To 5pm EST)
URL: www.gcpl.co.uk
Registered in England & Wales
Registration No. 2934719
Registered Office: 8 Baker Street, London W1U 3LL
[A BE (bioequivalence) study to 'determine' equivalence may not be
appropriate but a BA (bioavailability) study, as Andrew suggest, may
be very useful for studying the absorption process - db]
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