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Dear All:
I am moderating a round table discussion on "First time in Human
Dosing - Serendipity or Science" on Nov 12, 2009 between 9.00 -11.00
am as part of the 2009 AAPS annual meeting in Los Angeles. During
this round table discussion we would like to get an insight on
different strategies on arriving at first in human dose calculations
and designing first in human clinical trial. It is a good idea to
hear from the experiences of prominent speakers from FDA, and Merck
during this round table discussion.
This is an open floor model discussion encouraging active engagement
of everyone experience. If you want any questions or issues to be
discussed, please forward the questions in advance to my attention
via e-mail: drprasadtata.at.yahoo.com so that I will try to cover all
questions received in advance.
Hoping to hear from you soon.
Sincerely,
Prasad Tata
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The following message was posted to: PharmPK
Dear Sir,
Please explain about the various methods used to calculate dose for
first
time in humans and how we can calculate human dose from animal dose
M. Mohamed Hussain
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Hello
Try starting here:
Lowe et al (2007) Xenobiotica 37(10-11): 1331-1354
Regards
David Turner
Principal Scientist
Simcyp Limited
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Hello Mohamed,
Although it is not trivial to make first in human predictions, it is
possible. One requires reliable in silico estimates, in vitro values
that
can be appropriately converted to in vivo values (such as in vitro
microsomal clearance to in vivo clearance) and a good mechanistic
mathematical model such as those in Physiologically Based
Pharmacokinetic
(PBPK) models. We have one of the best simulation tools, called
GastroPlus,
which is widely used by almost all pharmaceutical R&Ds to make such
first in
human predictions.
Also, if you have in vivo (plasma concentration) data in animals, you
can
still obtain compartmental PK parameters for those species and then use
allmoteric scaling to obtain human clearnaces. However, if the PK in
these
animals is best described through multi-compartmental models, then
allometric scaling will be insufficient because the distribution
constants
(K12, K21) cannot be scaled up. Thus, you best option is to still use
PBPK
and obtain an in vivo clearance for the animals (against the Cp-time
data)
and then use allometric scaling to obtain an in vivo clearance value for
human and corresponding dose.
Kind regards,
Ray
Siladitya Ray Chaudhuri, PhD
Senior Scientist - Simulation Technologies
Simulations Plus, Inc.
42505 10th Street West, Lancaster, CA 93534
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Dear M. Mohammed Hussain,
The most successful method we've seen is the use of PBPK models.
Distribution is more readily scalable from animal than clearance;
however,
with both animal and good in vitro data, human PK can often (but not
always)
be predicted within about 2:1 for Cmax and AUC.
In a two-year study (of 21 in-house compounds that had data from
discovery
to human) reported by Pfizer at the ISSX conference in Shanghai last
year,
they showed prediction of human IV and PO PK from only non-human data
using
a variety of PBPK software as well as a previously used in-house
approach.
You can request the poster from the primary author, Susan Cole.
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 Mohamed:
Consider the maximum safe starting dose in initial clinical trials for
therapeutics in adult healthy humans (FDA guidance) and the one from
EMEA (strategies to identify and mitigate risks for first in human
clinical trials....)
Best regards
Nelida Mondelo
R&D Manager
Gador SA (Argentina)
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Dear Hussain,
You can either use PK sim or gastro plus software for the same or you
can use allometric scaling for the same.
With Regards,
Dr. Tushar Nahata
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Dear Hussain,
There are various methods available to determine the human dose from
animal data.
The most commonly used approach is to determine the Human Equivalent
Dose (HED) based on NOAEL obtained from toxicity studies and
conversion based on body surface area.
HED= NOAEL (Wt of animal/Wt of human)^(1-b).
Maximum recommended starting dose (MRSD)= HED/Safety factor
Please refer FDA guidance entitled "Estimating the Maximum Safe
Starting Dose in Initial Clinical Trials for Therapeutics in Adult
Healthy Volunteers" FDA, July 2005.
- Allometry has also been used to determine the human PK parameters.
- Some papers have also used PBPK approach for predicting the human dose
Thanks and regards
Tausif Ahmed, Ph.D.
Sai Advantium Pharma Ltd., Pune
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Dear Hussain,
You can either establish relations between physiologic parameters and
pharmacokinetic ones, compare between species and then extrapolate to
humans.
Best regards
Valva
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Dear All,
I have few doubts regarding the dose calculations !
Question 1 : FDA has given guidelines for the estimation of safe
starting dose in humans based upon body surface area !
Can the safe starting dose be always an efficacious dose ? if not what
are the approaches used to project efficacious dose.
Question 2 : i am trying to project the human oral pharmacokinetic
profile using " Cvss - MRT method " !
Can anybody explain me how to obtain the ka values using deconvolution
method in winnonlin (detail )?
Can , ka (absorption rate constant) values obtained by wagner nelson
method (curve stripping) instead of deconvolution, be used ?
Question 3 : How to obtain efficious starting dose in humans from PK-
PD modelling ?
Regards,
Raghav,
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Many thanks for an informative discussion.
For preference I would use more than one method and ensure that they
produce similar doses or work out the reasons if they don't. For
example, allometric dose calculations based on active doses in
preclinical toxicity tests would be one while another would be derived
from active concentrations in the animal models. An example of that
would be aiming to produce a selected fraction of the animal model MAC
in human plasma assuming say, a 7L plasma volume. That has the obvious
safety factor of the real volume of distribution being greater.
However, these factors don't seem to apply to immunologically active
molecules and I would be very interested to read about anyone else's
experience of them. How did they calculate initial doses and did
they learn anything from the Tegenero case for example.
Incidentally and counter-intuitively, I found that doing the IV
calculation made me more confident in the IV route than oral due to
being able to predict the plasma profile more accurately; even more so
if you have the ability to actually assay plasma during the study.
Andrew Sutton
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we evaluated compounds in rat and found huge hepatic extraction.
In fact after PO admin, no level was observed in plasma but well high
level in the liver at 8 and 24 hours?
This can be species dependant?
Thanks for your answer
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Hello,
If your compound is a substrate of some influx/efflux transporters and/
or subjected to enzyme mediated metabolism (usually CYPs) in liver
cells (hepatocytes), hepatic extraction could vary among different
species.
Here is an article by martignoni et al., which highlights the
significant differences in CYP mediated metabolism in among different
species.
Expert Opin Drug Metab Toxicol. 2006 Dec;2(6):875-94
Hope this could be helpful
Thanks
Ravi Talluri Ph.D
Sai Advantium Pharma
Pune
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Dear Mohamed Hussain,
I suggest that you have a read of the article, "Estimating the
starting dose for entry into humans: principles and practice" by
Reigner and Blesch, Eur. J. Clin. Pharmacol. 57, 835-845 (2002). This
comprehensive paper reviews various approaches, with example
calculations, employed at Roche for both cytotoxic and noncytotoxic
compounds based on preclinical findings (NOAEL, etc.). (Note: There's
a typo in the example on page 840. It should read: "Applying Eq. 6...")
You may also find of interest the slide presentation available (from
Roche again and includes PBPK modeling) at
http://mediaserver.aapspharmaceutica.com/meetings/DDS/Predicting_the_Human_Dosage_Regimen_from_Preclinical_Data_How_Confident_are_We.pdf
Best regards,
Peter
Peter W. Mullen, PhD, FCSFS
KEMIC BIORESEARCH (www.kemic.com)
Kentville
Nova Scotia, B4N 4H8
Canada
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Dear Mohamed Hussain
You may find the following paper useful:
Gibson CR, Bergman A, Lu P, Kesisoglou F, Denney WS and Mulrooney E
(2009)
Prediction of Phase I single-dose pharmacokinetics using recombinant
cytochromes P450 and physiologically based modelling. Xenobiotica
39:637 -
648.
Regards
Masoud
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Dear Mohamed,
I strongly recommend you to read and study the following two chapters
published in PHARMACOMETRICS (eds:Ene I. Ette and Paul J. Williams,
John Wiley & Sons, 2007):
1. Chapter 29. Chu et al. Designs for First-Time-in-Human Studies in
Nononcology Indications. pp.761-780, and
2. Chapter 30. Tranchand et al. Design of Phase I Studies in Oncology.
pp. 781-802.
You will find out a lot of very useful, already validated in clinical
practice, information and scientifically grounded recommendations how
to desing and perform a FIM study as well as efficiency-cost
comparisons of different study designs.
There are also appendices, attached to each chapter, with code for
exposure-A(dverse)E(vents) relationship figure, function codes for PK
profile and PK simulation and NONMEM code for allometric scaling.
I hope this info will be of help to you.
Have a nice weekend,
Dimiter
--
Dimiter Terziivanov, MD,PhD,DSc, Professor
Univ Hosp "St. Ivan Rilski",
15 Acad. Ivan Geshov st, 1431 Sofia, Bulgaria
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