If I would like to study the effect of a small molecule compound in animal, say rat. Do I need to conduct a dose-response study with 4 to 5 different doses in rats? Usually people find the maximum tolerated dose in animals based on toxicity endpoint and translated the MTD into first in human dose. Would conducting a dose-response study in animal to find out the dose-response/exposure-response relationship be useful to translate the dose range findings into human studies?
Dear Chenxiao Tang,
To check what is the role of MTD in FIM studies please download FDA guidance:
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
https://www.fda.gov/media/72309/download
Sense of dose/response studies explain next FDA guidance:
Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications
https://www.fda.gov/media/71277/download
" This exposure-response guidance focuses on human studies, but exposure-response information in animal pharmacology/toxicology studies is also a highly useful component of planning the drug development process (Peck 1994; Lesko 2000). "
" Biomarkers can also be useful during the drug discovery and development stage, where they can help link preclinical and early clinical exposure-response relationships and better establish dose ranges for clinical testing."
" Exposure-response data can be derived from these clinical studies, as well as from other preclinical and clinical studies, and provide a basis for integrated model-based analysis and simulation (Machado et al. 2000; Sheiner and Steimer 2000)."
" It emphasizes the importance of conducting an integrated analysis of all clinical and preclinical exposure-response data that forms the foundation for dose and dosing regimen determinations and dose adjustments for subpopulations. "
Hope it helps,
Best regards,
Tomasz
Studying at least three different doses gives you an idea of therapeutically effective concentration range which might be far away from MTD. I would personally suggest different dose studies for phytochemical or the drug for newer indication
Dear Chenxiao Tang,
When studying new drugs, the researcher must understand how the effect depends on the dose. If the effect does not change with increasing the dose, the compound can not be a drug, because the doctor will not be able to control the treatment process. You don't have to take a lot of doses. 2-3 is enough. But it is very important that the range between therapeutic and toxic doses is large enough. All this should be determined in animal studies, so that in clinical trials, the doctor could understand what his room for maneuver.
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