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The following message was posted to: PharmPK
Hi,
I am working with several oncology compounds that we
had to dosing i.p. with a suspension (slurry) using
50% PEG/saline as vehicle for ~21 day efficacy study.
The compound/slurry precipitated on the organs and
caused chemical peritonitist that actually resulted in
animal death. Did anyone had similar experience and
how did you solve the problem? These compounds are
highly soluable in DMSO (>100 mg/ml). And DMSO vehicle
has been used for oncology Xenograft models quite
often in the literature. But I heard that DMSO can
affect metabloic enzymes in the liver, though I could
not find a thorough study on PubMed on this topic.
Would the small amount of DMSO (<50 ul/dose)
significantly affect the metablolism of my compounds?
Does it matter if I am just trying to see whether
these compounds have any efficacy in vivo?
Thank you for your help in advance.
Xiaobing Qian
An in vivo biologist in Connecticut
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The following message was posted to: PharmPK
If you are having precipitation problem with PEG/saline; you would also
have precipitation problem with DMSO. It is best to reformulate your
drug in Cremophor-EL or other formulations. For simple efficacy study
you are probably OK with the DMSO formulation, however (keeping in mind
the potential toxicity with drug precipitation).
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The following message was posted to: PharmPK
Hi,
this precipitation of the active is a very common phenomenon with this
kind
of cosolvent formulation.
What you should envisage is the use of a surfactant (Tween 80,
Cremophor EL,
etc.) that gives more stable formulations. One simple experiment is to
test
your formulation by diluting it into some pH7.4 buffer to anticipate any
precipitation in vivo. Basically you could evaluate a 1:1 and 1:10
dilution
into appropriate buffers.
You should also evaluate the use of a SR device such as an Alzet
micro-osmotic pump that should be implanted there.
As you explain the study is designed to only demonstrate the efficacy
of the
active. In these conditions all you need to care about is that the
plasma
drug level is high enough to ensure its pharmacological activity. So you
have to ensure that the active remains solubilized at the "injection"
point
and that it is well absorbed per ip.
I hope this helps,
Frederic
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The following message was posted to: PharmPK
Hi,
While I agree that cremophor EL might well solubilize the compound
sufficiently for IP injection I would just say that it causes severe
anaphylactic reactions in man and is not a justifiable candidate for
formulation in the longer term. It also causes histamine release in dogs
manifest by swelling and itching of the muzzle. I don't know if it
causes
similar responses in other species.
Andrew Sutton
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The following message was posted to: PharmPK
HI
Just a quick note. Cremophor is used in several marketed drug
formulations,
including Taxol and Synercid. So, its use is not necessarily the kiss
of
death for a clinical product.
Cremophor causes the worst reactions in dogs. Hence, preclinical
testing
will usually not include that species as the non-rodent species. For
example, Synercid utilized rats and monkeys for the preclinical toxicity
testing (data available in the Summary Basis of Approval in the FDA
website
under the Freedom of Information Act).
Hope this helps!
Jeffrey L. Larson, Ph.D.
Director of Toxicology and Pharmacokinetics
Tanox, Inc.
4888 Loop Central Drive
Houston, TX 77081-2225
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