With in vitro studies, we are selecting some IC- 50 values for active principles or drugs which are available as such. By MTT or by some other assay, we are identifying the IC-50 value for the particular drug. Each drug has a different value based on the drug efficacy, I need to know up to which concentration we can consider it as a good one, which can be used for further processing.
for a first orientation the qoutient between the highest concentration that is not toxic in normal "control" cell and the concentration that is effective (toxic) in cancer cells should be helpful. For the (long) way to "first in human" I recemmend the EMA guidelines (guideline for cancer attached, basic general guideline in second post)
@ Asia Naz
A very VERY rough first estimate is based on the assumption of a perfect distribution in vivo. Then 0.2 mg per L should be the same as 0.2 mg per kg bw. As we usually do not know the most sensible tissue in vivo I would divide by ten for a starting dose, that is start with 0.02mg/kg. The first idea on toxicity in vivo is usually given by acute toxicity. I attach a file of a standard approach that shows how this can be done with a minimum of animals.
Arun,
Before taking the compound to the animal for testing do in-vitro stability assays in microsomes and PK studies
Thanks for your valuable comments, but still there are some clarifications. Is there any any range to be consider as a drug for a particular compound. for example some drugs have low IC-50 values with more anti cancer properties. suppose, for a drug IC-50 ranging from 500 to 1000 micro moles will be consider or not.
If the compound is having IC-50 in this range in primary biochemical assays I think it will be difficult in in-vivo to get a good PD effect at a reasonable dose. Please check this EC50 in the cell based assay data first. But, still the dose and the efficacy of the compound will depend on its target and indication.
@Arunkumar Ramachandran
I suggest there are two points to consider:
1. Selectivity: A substance that has an anti-cancer effect (in vitro!) at very high concentrations only is rather unlikely to be sufficiently selective for cancer cells. With higher concentrations effects on other cells (or in vivo on other tissues and organs) become increasingly more probable. Promising active substances will (usually) work in low concentrations. There is no absolutely prohibitive rationale why a drug that is effective close to the micro-molar range only cannot be used for cancer treatment. From experience, however, we know that clinically useful drugs work at much lower concentrations. Therefore most would not regard it as a suitable candidate for development.
2. Feasibility: there is a maximum amount you can give to a patient. If it is the oral route, doses of tens of grams are not acceptable. If it is the parenteral route, the mere volume is a problem – especially when the substance is poorly soluble.
@Asia Naz: click on it, it should open in a new window. If this does not work for you let me know then I send you the file.
There are many other factors like solubility of compound whether compound is hydrophobic or hydrophilic (Solvent needed to dissolve the compound), its half life, tissue distribution, Bio-availability etc
hii
Please guide me regarding :
I have a similar situation wherein the effective inhibitory conc of the compound in vitro was 0.04% v/v and 0.08%v/v. i want to test the compound it in mice (weighing 30-35mg) thru oral feeding. what conc (ie %) should i use. My LD50 studies using oral route is 10ml/kg ie greater than 9257.50 mg/kg.
Hi Arun, Please guide me on this. Currently facing this problem. Let say from in vitro study (MTT Assay) i have selected IC50 value example 4uM. How to convert this to in vivo mice model in mg/kg?
IC50 dose in vitro is nothing related to in vivo test.
it is too much different and you cannot apply in vitro dose for in vivo.
Thank you Mingchuan Yu for that comment. The question i have is how do you translate the IC50 you have in vitro to in vivo? Say the IC50 in vitro was 0.5 ug/ml to what does this translate into in vivo?
Cornelius Ssemakalu, as I mentioned there previously, in vitro IC50 is nothing to do with in vivo IC50 totally. They are two different stories.
If you want to get IC50 for in vivo, you must do from the scratch and get LD100, LD50 and then reduce dose slowly to get IC50 of the same drugs or compound that you used for your in vitro tests.
We are not doing in vitro test IC50 to get IC50 dose of in vivo and no one can convert it by no means at all. Hope this helps.
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