I would like to know what is more important when we talk about drug discovery /pharmacology. Dose dependent response curve or dose independent response curve. And which one in any specific case
Having dose dependent activity is good for a drug than dose independent activity. Safety or toxicity issues will arise by later one as we unable to predict intensity of action while increasing dose
I would consider both criteria of the same importance, as both are providing key informations for a successful drug development campaign.
Dose-dependent activity is usually the first criteria we look for in a lead drug prototype to answer. The fundamental reason for such criteria is that we are screening our compounds at lower (also called therapeutical) doses, which should show a direct relationship to a biological response. The proper distribution of a dose-response curve will provide an index (IC50) which reflects the specific dose able to cause 50% of the biological response. This index can be used to compare the potency of different drug prototypes in the same system - Where those with the smaller index values are the most potent. As you keep increasing the dose of your compound to observe its biological outcome, you will eventually reach a dose that saturates the system. It means that from that point, increasing the dose even further is meaningless, as the compound will start to display a dose-independent behavior.
Finding the proper range of drug-independent behavior is of fundamental importance to define your boundaries for each specific study. This is of major significance in animal studies to access the in vivo toxicity of a drug for example, where usually high doses are applied:
Toxicity at high doses may be due to saturated detoxification or excretion mechanisms which when fully operative at lower doses do not result in the same toxic response. Therefore knowing the dose deviations (boundaries) from linear, dose-independent, and dose-dependent activity precludes extrapolating the same toxicity from high to low doses. Example: If the system is saturated at 340mg/kg and you test 720mg/kg, you will see a dose-independent behavior, which does not mean 720mg/kg is equaly toxic to 340mg/kg. You will know that if you learn that 340mg/kg is your limiting dose between dose-dependent and dose-independent activity.
Dear Dr. Andre, Thanks a lot for the information. But for suppose, we have two test samples A and B against response X. Sample A is showing steep down curve with an IC50 value of 1 microgram/ml and after that at 85% inhibition it is getting saturation and further increase of dose to even 100 microgram/ml doesn't effect and remains a platue phase. While on the other hand, Sample B is having proper slope of inhibition showing dose dependent response curve but IC50 value is 10 microgram/ml and even saturation is not coming in this case till 100% inhibition. So what would be the ideal condition, is it better to move forward with sample A or Sample B, or shall we consider both. Which one will be more appropriate?
I would suggest to go with both the samples and perform toxicity studies. My interpretation of the condition says that microorganism are more sensitive to sample A but more responsive to sample B. Also, sample B which is exhibiting a dose independent activity might be a bit difficult to handle in further phases in terms of optimization and since the IC50 of sample B is more, it clearly suggests that it is more efficacious but less potent whereas sample A is more potent but less efficacious. I think, you must go with both the samples for toxicity studies. It would probably be more clear as to in which direction you have to proceed after you have toxicity results in hand.
Thanks Dr. Suchita, but in terms of potency, we can't claim right now. As Sample A is crude extract and sample B is pure molecule. Sample B has IC50 value of 7 micomolar which is much below to pass for any molecule for drug i.e. 25 micromolar in general. In case of Sample A, it may be possible the the single responsible molecule has activity in nanomolar range and it may be that many molecules in together give that response. So in case of sample A, we need to first isolate all molecules doing bioactivity guided fractionation, while in case of Sample B, we have pure molecule in hand. So what to do in this case.
I thought you are dealing with pure compounds. In that case, the comparison would be defintely irrationale unless the pure compounds are isolated and tested in sample A also because in a crude extract, there are "n" no of compounds which are responsible for modulation of biological activity. Can you please let me know in more detail about what activity are you performing and on what strains.
I think the attached file can throw some light on your problem. This paper is on "Pharmacokinetic and Pharmacodynamic Considerations in Antimalarial Dose Optimization". It deals with the key points that must be considered while picking a concentration that can turn out to be effective in dealing with malaria in later phases of DD process irrespective of dose dependent or dose independant nature of molecule. Also, if you are able to isolate the pure compound from sample A, then you can go for testing "FIXED DOSE COMBINATIONS" of sample A+Sample B by hit and trial. If that has an optimzed effect, then you can obviously go further with that FDC.
I am experiencing the same problem, my extract has a strong anticonvulsant activity but not dose dependent, infact the lowest dose afforded the highest anticonvulsant property. Please, help me explain this
I would suggest to go with both the samples and perform toxicity studies. My interpretation of the condition says that microorganism are more sensitive to sample A but more responsive to sample B. Also, sample B which is exhibiting a dose independent activity might be a bit difficult to handle in further phases in terms of optimization and since the IC50 of sample B is more, it clearly suggests that it is more efficacious but less potent whereas sample A is more potent but less efficacious. I think, you must go with both the samples for toxicity studies. It would probably be more clear as to in which direction you have to proceed after you have toxicity results in hand.