Hello everyone!
I would very much appreciate any help with the following. I have some experimental compounds which have never been tried in animal studies before, and have no close analogues. The only usable information about them are their LD50s (for mice), and I need to calculate appropriate doses for an experiment in rats (we are to evaluate efficacy, not toxicity). What would be the best approach to converting an LD50 to a presumably therapeutic dose for animals? Any advice would be super helpful.
Thanks in advance!
Dear Veronika,
Please check excellent power point by Jennifer Sims from EMA workshop. Hope it will be useful for your research. Please check graphs which explains what place in tox/pharm development have therapeutic range. I think you can use that sources to optimize your work with animal models. Its really hard to justify ED50 based only on LD50 data, please check sources below.
Calculation of the Minimum Anticipated Biological Effect Level (MABEL) and 1st dose in human
https://www.ema.europa.eu/en/documents/presentation/calculation-minimum-anticipated-biological-effect-level-mabel-1st-dose-human-jennifer-sims_en.pdf
presentation by Bruno Boutouyrie-Dumont and some papers:
Dose selection based on Minimal Anticipated Biological Effect Level (MABEL) for biologicals and high risk small molecules: case studies & discussion
https://www.eufemed.eu/wp-content/uploads/Bruno-Boutouyrie-Dumont.pdf
Article Determination of the starting dose in the first-in-human cli...
Best regards
Tomasz
Tomasz Grabowski, thank you so much for your help! I believe this might be the closest to what I've been looking for. And thank you for attaching all the links, that's very considerate of you!
here there is no direct relationship between toxicity and therapeutic effect, so it is impossible to predict a therapeutic effect from LD50, but you can do preliminary tests using concentrations much lower than the LD50 for example LD50 / 10 or LD50 / 20 or LD50 / 100.... good work
Wafa Tayeb, thank you for your reply! What we need is just the first dose to try out, and we want it not to be chosen purely randomly, but with at least some justification in mind. So what you've suggested sounds very reasonable, we should definitely do that!
Veronika, you can make your own dose-response curve, as it is a sigmoid s-shaped curve based on the exponential part of it ( usually between 25 -75% aprox.) you probably extrapolate the other points , they are decimal log doses x a percentual reponse . Thus you may construct your graphs. Good look.
Luiz Querino Caldas, thank you for replying! What you're suggesting seems a bit more than we've originally planned to do, but maybe we'll be able to make use of it, so thank you!
Use a method Up – and – Down method ( Dixon, 1980 )10 laboratory animals can be used to determine LD50 When you get the way, we can discuss how to calculate if I need helpز
Ashraf S. Alias, we already have the LD50 value and are looking forward to assessing the efficacy of the substance, but thanks for replying and for the message you've sent me!
I am happy to help any researcher who needs information for the purpose of doing his research and thanks you for your nice words
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