Hi, I am trying to design a study to determine the MTD of a small molecule on rats. Due to the poor solubility of our compound, the maximum dose for single injection were limited to 50 mg/kg, IV. To satisfy the requirement of ICH guideline, should I set a multiple dosing to satisfy the higher dose like 100 or 150 mpk? If so, the MTD should be determined as the Cmax or as the total dosing?
Not sure I fully understand your question. Normally, single ascending dose (SAD) study will be conducted followed by multiple ascending dose (MAD). DLT (dose limiting toxicity) should be predefined. An MTD will be determined if DLT is occurred >30% subjects (probability). If PK samples are collected, Cmax and AUC should be both calculated. Basically, in your SAD study , you can try different dose levels e.g., 5, 15, 30, 50. In your multiple dose study, you need to determine dosing interval, then try the MTD in SAD with multiple doses.
If I understood the question in general from my experience I would have acted like this:
maximum single dose - the largest amount of the drug during the regular treatment regularly causing toxic phenomenon, and has a positive therapeutic effect (typically three to four times is a value medium therapeutic dose)
- maximum daily dose - the largest amount of the drug taken in the time period of 24 hours, does not cause toxic phenomena (typically amounts to three times the maximum single dose) to achieve the desired daily your project maximum tolerance dose (MTD)!
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