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Dear all,
We would like to conduct a phase I clinical study in order to
determine the maximal tolerated dose (MTD). For a drug that is not
well tolerated due to GI effects (nausea and vomiting), a titration
study could help to determine the MTD. Is there any specific/standard
design to do such a study? What about the number of doses that should
be used, the incremental titration regime?...
Your help is greatly appreciated,
Samia
__
Samia Ezzine, D.Pharm, M.Sc, Ph.D
Pharmacokinetic Scientist
Preclinical Research and DMPK
Neurochem Inc.
275 Armand Frappier Boulevard
Laval, Quebec, Canada
H7V 4A7
Tel: (450) 680-4441
Fax: (450) 680-4505
sezzine.-a-.neurochem.com
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Dear Samia
Generally, first in human studies are always done with single doses.
The doses are escalated to higher dose level to determine the MTD.
Once the MTD is determined in Single Ascending dose study, you can
plan for multiple ascending dose study. If your molecule is having
property of GI irritation as side effect and if you feel that healthy
volunteers can't tolerate even single doses, then it is worthwhile to
take a go/no go decision on that molecule. Of course it depends on
therapeutic area that molecule is belongs to. According to my
knowledge, there are no dose titration study designs are available in
the literature for first in man studies. You can try such design in
multiple ascending dose study, if the compound is well tolerated in
single ascending dose studies.
D Mallikarjuna Rao
Principal Scientist-Clinical Development
Discovery Research
Dr. Reddy's Laboratories Ltd.
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The following message was posted to: PharmPK
Dear Samia
You could try giving the drug with food which may help with the
nausea. You can use a titration scheme in your MTD study, but only
if you plan on using a similar scheme in the Phase II and III
trials. The titration would depend on what doses from previous
experience that you know do not produce nausea, etc and what you
think is practical for Phase II-III studies, but in general, any
titration scheme should be helpful in increasing tolerability. While
titration is routinely done in clinical practice for several drugs,
the Marketing dept doesn't favor it as it is perceived to be a
negative when selling the drug.
Regards
Suresh
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The following message was posted to: PharmPK
Dear all,
Samia Ezzine wrote : "We would like to conduct a phase I clinical
study in
order to determine the maximal tolerated dose (MTD). For a drug
that is
not well tolerated due to GI effects (nausea and vomiting), a titration
study could help to determine the MTD. Is there any specific/standard
design to do such a study? What about the number of doses that should
be used, the incremental titration regime?..."
I have found that nausea is accompanied by delayed gastric emptying.
We can
measure this for liquids repeatedly in healthy volunteers at low cost
with
the non-invasive method of epigastric impedance. It would provide
objective
data on the limit of tolerability without deliberately making subject
vomit,
which I consider to be unethical.
With epigastric impedance it would be a simple job to measure gastric
emptying in an ascending dose design with the intention of stopping
the dose
when the gastric emptying becomes significantly delayed. For example
a small
dose of 0.09mg/kg morphine iv ( = 6.75mg to a 75kg individual) has been
shown to almost quadruple gastric empting. Means for a test "meal" of
500ml
water were 5.5 +/-1.9 mins , n = 11, on placebo and 21.+/-9.0 mins, n
= 11,
after morphine. This was obtained whilst causing a significant but
tolerable
amount of nausea.
As it is non-invasive we can use a crossover design and compare up to 3
active doses with placebo, thus increasing the sensitivity of the
design, a
useful aspect when investigating a system as variable as the GI tract.
Samia's study would be stopped at a predetermined level of nausea. It
could
be perhaps "Marked" on a Likert scale that would comprise: none,
trace,
mild, moderate, marked, severe and vomiting.
I hope this is helpful.
Andrew Sutton
URL: www.gcpl.co.uk
Reference. Murphy DB et al 1997. Anesthesiology. 87: 756-770.
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