Back to the Top
Dear Members,
When we have an insoluble NCE which is active, how do we go about
preclinical toxicity studies where we have to give large doses of the
compound intravenously.
In the process of increasing the solubility to meet the requirements
of IV dosing, we usually incorporate cosolvents and surfactants like
DMSO, DMA, pharmasolve, cremophore, solutol etc, may be in the high
concentrations, which may be not advisable in clinic. In some cases,
preclinical studies show some acute toxicity due to local irritation
and quite often because of the large volumes administered.
Can you suggest us any kind of justification in these situations, as
the formulation that will be taken up for clinical studies is different?
Can we use use the vehicle (blank formulation) treatment to justify
the toxicity of the formulation?
Do we need to use the same formulation in clinical studies, Which was
used for preclinical tox studies?
Look forward to hearing from you
Thanks and regards
Varma
Dr. Manthena VS Varma
NDDS-Pharmaceutical R&D,
Nicholas Piramal Research Center,
1, Nirlon Complex, Off Western Express Highway,
Near NSE Complex, Goregaon (E),
Mumbai-400 063, INDIA.
email: varma_mvs.at.yahoo.com or vmanthena.-a-.nicholaspiramal.co.in
Phone: +91 22 3081 8914; +91 932 426 9193
Back to the Top
The following message was posted to: PharmPK
Dear Varna
I have the same problems, i wonder if there are a "official
recommendations, FDA , EMEA" for vehicles for IV, Oral, and IP,
more than
for PK studies for TOX studies with longer treatments.. For Oral
I used
CMC, or Agar but sometime i found some toxicokinetics with very
unusual
behaviour in absorption phase.
Another question related with this, is about that if the analytical
methods for analyse formulations in TOX regulatory studies have to be
formal validated?.
Thank
**
Benjamin Santos Ph.D.
Pharmacokinetics and Metabolism Dept.
R&D Center, Ferrer Internacional S.A.
E-mail bsantos-research.-a-.ferrergrupo.com
Back to the Top
The following message was posted to: PharmPK
Dear Varma,
The formulation strategy for IV delivery of insoluble
NCE has undergone significant changes with respect to
the conventional approach of dosing clear solutions
only .( Please refer approches Muller etal).Most of
the organic solvents has restrictions on the use for
repeat dosing for 14 days or 28 days tox. Hence the
best approach would be to avoid or decrease the
cosolvent quantity in tox formulations.
Cyclodextrin is a useful alternative.Although HPBCD
has nephrotoxicity at high dose levels the sulfabutyls
ether derivative is safe. However it is essential to
study the kinetics of complexation and confirm PK
exposures in desired species before initiating tox
studies.
Nanosuspension is another way to deliver high dose
of NCE for IV with out use of harsh co solvents.But
the plasma solubility,protein binding and volume of
distribution of the compound should be favorable for
supporting the use.The clearance should not be altered
significantly due to the formulation.
However the formulation preparation and
characterization needs in depth evaluation and
optimization.
The projected human dose is much less that that for
preclinical tox studies.Hence the formulation for FIH
would generally not require use of cosolvents (In
high levels) and can be aqeous based.
thanks,
Back to the Top
Dear Dr. Varma,
As per my limited knowledge, no guidelines has specified about
maximum dose of IV route for acute studies, if you have NCE and for
prilimanery testing you have to do tox studies (only to generate data
to support your research), you can take help of your formulation
department to get maximum possible higher concentration in mL, but if
you have to go for regulatory permissions then you can't use any
other vehicle without including a extra group of that perticular
vehicle which have been used to make that formultion. for regulatory
porpus also they says that you can use maximum possible concentration
to derive tox data and i m also from india so i can say if you
provide suported data for your problems they will not make you in
problem. some time you can do MTD also rather then acute in some
conditions.
as per me ... "The main thing in tox study is how you present your
data to regulatory body".
Thanx & regards
Chintan Patel
Cadila Pharmaceuticals Ltd.
Back to the Top
Hi Members,
Thanks for the suggestions dear Dr. Chintan Patel
Its been long time for us working on developing an IV formulation for
a practically insoluble NCE. We have tried various approaches and
came with some solutions.
The science we followed was to do the solubility studies of this NCE
in various co-solvents and in the presence of certain surfactants
that are approved in the clinic. In this process we came up with some
IV solutions which can hold the compound upto 100fold high
concentrations then its actual solubility. However, even when the
surfactant concentrations is as low as 5%, we noticed some kind of
acute adverse effects in rats (5ml/kg) and mice(10ml/kg) and is
certainly worrysome to our biologists.
I was very surprised to see such kind of reactions with surfactants
like solutol HS 15 and cosolvents like NMP. Mice died when we
injected only (without NCE) 5 %NMP or 5% solutol HS 15 in saline
(10ml/kg individually). I wonder if this is really safe in humans...?
However, there are formulations (Vit K1) that contained 50% solutol
HS 15 and can be administered IV.
I would like to know members` experiences with these kind of
cosolvents and surfactants.
Thanks and regards
Manthena VS Varma
Nicholas Piramal India Ltd. INDIA.
Back to the Top
The following message was posted to: PharmPK
For general information about safety and toxicity of a lot of
chemicals, including pharmaceutical excipients, you can freely look
at TOXNET, the databases on toxicology, hazardous chemicals,
environmental health, and toxic releases of USA-NLM
http://toxnet.nlm.nih.gov/index.html
or at IRIS Substance List (IRIS is the Integrated Risk Information
System of US Environmental Protection Agency)
http://www.epa.gov/IRIS/subst/index.html
Best Regards
Stefano Porzio
Inpharzam Ricerche SA
Zambongroup
Switzerland
Back to the Top
The following message was posted to: PharmPK
Hi Chintan/Manthena,
There are guidelines for all form of drug
administration in laboratory animals. Please refer to
J. Appl. Toxicol. 21, 15-23(2001). Regarding the
toxicity of approved excipients in mice/rats/monkeys
etc, you may have to refer to the Textbook of
Pharmaceutical Excipients or contact the manufacturer
for literature. There you can find the top dose etc.
Response also varies with fast iv bolus vs slow iv
injection (infusion). I am not sure how Vit K is
administered to human in clinic.
Hope this helps.
Jagdish
--
Jagdish Jaiswal, PhD
ADME Pharmacologist
Auckland Cancer Society Research Centre
The University of Auckland
Private Bag 92019
Auckland
New Zealand
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)