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The following message was posted to: PharmPK
Dear all!
I have a question regarding the choice of dosing intervals in repeated dose toxicity studies. According to on my rather limited knowledge on this topic, the dosing interval in these kind of studies is frequently based on practical considerations and/or on recommendations from corresponding guidelines (e.g. EMEA/CHMP/SWP/488313/2007: [...] Generally, once a day administration is adequate. In some cases more frequent administration in animals than anticipated in clinical use may be appropriate [...])
I would be happy to receive suggestions for a rationale regarding the choice of dosing intervals in these kinds of studies. I encountered two possible justifications for choosing a dosing interval:
1. Should only Cmax values of a potential toxic dose reach the minimum toxic concentration after each administration? This can be achieved by using dosing intervals that are 5-7 times the terminal half-life as after 5-7 times the terminal half-life a substance is practically eliminated from the system. With potential toxic doses the minimum toxic concentration is reached following each administration but not with a potential safe dose.
2. Should there always be a concentration above the minimum effective concentration during the whole course of the study? Repeated administration when a residual concentration from the previous dose is left in the system causes accumulation until a steady state is reached.
3. ?
According to my opinion, there is one drawback with option 2, namely that accumulation can increase concentrations above the minimum toxic concentrations even for low doses being safe. Additionally, interpretation of study results may be difficult as an increased AUC after repeated administration compared to first administration a) may indicate a damage of the elimination system and a subsequent reduction in clearance and/or b) may indicate nonlinear PK. In case of an increased AUC, it is therefore difficult to distinguish between anticipated accumulation, damage to the elimination organs or nonlinear PK.
According to my opinion, there is also one drawback with option 1, namely by using rather long dosing interval, a repair of tissues may occur as there is sufficient time between study drug administrations.
Any suggestions and/or points of views are highly appreciated!
Martin
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Martin,
Exposure margins (generally AUC driven, but in some cases, target dependent they can be Cmax driven) that will allow you to assess toxicity in your most sensitive species is the general aim of the repeated dose toxicity studies. Have you conducted a single dose tox assessment to evaluate the MTD for the calculation of your start and range doses? Also the other aspect to consider with dose and dosing intervals is the target and any target related toxicity you may encounter. Oncology targets, for instance, then to have a lag period that would require an MTD to be conducted for up to 5 days of dosing/observation. Using a 1 day approach can result in a flawed study with deaths in the high doses, leaving you with a much lower dose range for your repeat dose.
-- Sanjeev Thohan, PhD
SARx Consulting
SARxconsult.at.Gmail.com
http://www.linkedin.com/in/sanjeevthohan
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The following message was posted to: PharmPK
Dear Martin,
The dosing intervals in tox studies are determined based on the proposed
dosing intervals in the clinic. For example, if you are proposing
once/day dosing for 2 weeks in the clinic, then you need to dose
once/day for a minimum of 2 weeks in the tox studies. On the other
hand, if you are proposing to dose once/week for a 2-hr infusion in the
clinic, then you need to dose once/week for a minimum of 2-hr infusion
in tox.
The dose strategy in the clinic is set by a number of variables,
including dose strategy in efficacy models, stage of development (i.e.
Phase I in health volunteers vs Phase II repeat-dose study), etc.
Mary
Mary M Sherman, Ph.D.
Aptuit Consulting, Inc.
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