Maximum tolerated dose (MTD)
The highest dose of a drug that patients can take without too many severe side effects, traditionally the target of phase 1 trials and the dose carried into later trials. For chemotherapy more was better; for targeted drugs and antibodies the best dose is often lower.
Classic dose-finding assumed efficacy and toxicity rise together, so the MTD was the dose at which about a third of patients had dose-limiting toxicity. Many targeted drugs and biologics saturate their target well below the MTD ('MTD not reached'), and approving at the MTD has led to poor tolerability, dose reductions in half of patients and post-marketing dose changes (sotorasib 960 vs 240 mg, belantamab, cabozantinib). Project Optimus (FDA, 2022) now expects randomised comparison of at least two doses before pivotal trials to identify an optimal rather than maximal dose, and the recommended phase 2 dose is chosen on exposure-response, not toxicity alone.
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