Maximum Tolerated Dose (MTD)
The highest dose that can be administered without causing unacceptable toxicity, typically established in Phase I dose escalation trials. The MTD defines the upper boundary of the therapeutic range but is not necessarily the optimal dose — many drugs work best at doses below the MTD.
Technical Context
MTD determination uses formalised dose escalation designs. In the 3+3 design: MTD = highest dose where ≤1/6 patients experience DLT. In model-based designs (CRM, mTPI, BOIN): MTD = dose closest to the target DLT rate (typically 20-33%) based on accumulated dose-toxicity data modelled using Bayesian or likelihood methods. For peptide drugs, the MTD established in Phase I may not be the therapeutic dose — many drugs are most effective at doses below MTD. The optimal biological dose (OBD) concept is increasingly used alongside MTD, particularly for targeted therapies where maximum efficacy may plateau before maximum toxicity. GLP-1 RA dose titration schedules essentially implement a personalised MTD approach — patients escalate to the highest tolerated dose within the approved range.