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Dear Sir,
A question relevant to the calculation of therapeutic
index for antitumor drugs. Is that correct to express the TI as the
ratio between exposure (AUC) at toxic dose in a tox species ( Rat )
and the exposure in a pharmacological model specie ( mouse ) at active
dose?
What is the best way to express this parameters? Using doses in the
same model ( mouse for example ratio between LD10 and Dose at 50%
activity) or using exposure ?
thanks
Cecilia Allievi
CTI-Inc-Bresso
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This sort of calculation gets a bit muddy because the therapeutic
action itself is likely to induce adverse effects. This can lead to a
sterile discussion on what are acceptable adverse effects. While the
TI is useful in deciding the starting dose for a new medicine designed
to treat a non-malignant condition, it is not so useful for an anti-
cancer agent.
What usually happens in a clinical trial of an anti-cancer agent is
that the dose is increased to the point that produces patient
intolerance and any therapeutic effect is assessed at that level. In
this context, the concept of a therapeutic index is not appropriate.
Nonetheless the approach you suggested is sound way of ticking the TI
box - don't forget to use units of mgs/ m2. It is customary to
compare doses of anti-cancer agents using body surface area rather
than body weight. Unfortunately this has the effect of reducing the
margin!
Yours sincerely
Ian Smith, BSc, PhD, DipRCPath (Tox).
Principal, ASIS Solutions.
E: Ismith1945.-at-.aol.com
A: 4, Greenfield Way, Cuddington, Northwich, CW8 2YH, UK
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Dear Cecilia
It is normal practice to use dose rather than exposure for calculating
TI from particular xenograft animal model. Determine MTD dose and ED50
from same animal species and use the equation to calculate TI
TI=Maximum Tolerable Dose/ED50
Regards
Venkatesh
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The following message was posted to: PharmPK
Dear Ian,
You wrote:
> don't forget to use units of mgs/ m2. It is customary to compare
doses
> of anti-cancer agents using body surface area rather than body
weight.
> Unfortunately this has the effect of reducing the margin!
Could you please be more clear and specific about this last sentence? I
don't understand what you mean. Which margin do you mean? And if this
effect
is 'unfortunate', why should one use mg/m2 units? Or is it that using
mg/m2
units results in a more precise, and so possibly more narrow therapeutic
index? If so, this would not be 'unfortunate'. Do you have references to
support your statement?
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Email: j.h.proost.-at-.rug.nl
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