What is the maximum tolerated dose (MTD) of a drug in medical treatment?

Maximum Tolerated Dose (MTD) in Medical Treatment

The maximum tolerated dose (MTD) is the highest dose of a drug that does not cause unacceptable side effects or toxicity during medical treatment, traditionally defined as the dose level at which no more than a predefined percentage of patients experience dose-limiting toxicity. 1

Definition and Concept

The MTD concept originated from early cytotoxic chemotherapy development, where several key assumptions guided dosing strategies:

• A dose-response relationship exists for efficacy
• The therapeutic window is relatively small
• Toxicity (primarily myelosuppression) correlates with drug exposure and efficacy
• Higher doses were preferred due to rapidly progressing chemosensitive disease 1

For decades, the recommended phase II dose (RP2D) was generally set at or near the MTD, particularly for cytotoxic agents where reduced doses were associated with inferior outcomes 1.

Determination of MTD

The MTD is typically determined during phase I clinical trials through dose escalation studies using various methodologies:

• Traditional 3+3 Design: Escalation in cohorts of 3-6 patients until a predefined percentage experience unacceptable toxicity 2
• Model-based Designs: Using pharmacodynamic models to more accurately estimate MTD with fewer patients and greater precision 2
• Bayesian Adaptive Designs: Continuously updating dose-toxicity data to guide dose escalation decisions 3

For combination therapies, specialized approaches are needed:

• The MTD exists as a "contour" rather than a single point, requiring two-dimensional dose-finding strategies 4
• Designs like the "waterfall design" divide the task into sequential one-dimensional dose-finding processes 4

Evolution of the MTD Concept

The traditional MTD-based dosing paradigm has evolved significantly in recent years:

• For targeted agents and monoclonal antibodies, the optimal dose is not necessarily the MTD 1
• MTD-based dosing can result in unnecessary morbidity and potentially fatal toxicity 1
• For protein-based therapeutics like monoclonal antibodies, phase I studies may never reach an MTD 1

Modern Approach to Dose Determination

Current guidelines recommend a more nuanced approach to dose determination:

• Recommended Dosage Range (RDR): Rather than a single MTD, defining a range of effective doses based on:

  • Toxicity/tolerability
  • Efficacy
  • Pharmacokinetics
  • Pharmacodynamics 1

• The RDR should include at least two dosages:

  • The lowest level where reproducible activity is observed
  • A higher active dosage associated with toxicity (which may approximate the MTD) 1

• The minimal reproducibly active dosage (MRAD) and maximum administered dose (MAD) help define this range 1

Clinical Applications and Considerations

Different therapeutic contexts require different approaches to MTD:

• Chemotherapy: Dosage is limited by impact on normal bone marrow cells, requiring protocols designed to allow for bone marrow recovery between cycles 5

• Antifungal Therapy: For drugs like posaconazole, voriconazole, and itraconazole, therapeutic drug monitoring is recommended to maintain levels within a therapeutic range while avoiding toxicity 1

• Chronic Disease Management: In conditions like coronary artery chronic total occlusion, maximally tolerated doses of optimal medical therapy are indicated before considering interventional procedures 1

Pitfalls and Limitations

Important caveats to consider when applying the MTD concept:

• Early clinical trials are often limited to highly selected patient populations 1
• Protocols may only consider toxicity from the first one or two cycles, though some drugs elicit >50% of severe toxicities after the dose-limiting toxicity period 1
• Patient perceptions of chronic mild to moderate symptomatic adverse events are often not considered in dosage recommendations 1
• Many drugs are routinely used at doses lower than those in product monographs/prescribing information due to tolerability issues 1

Modern Recommendations

The European Society of Medical Oncology (ESMO) now recommends:

• Focusing on a recommended dosage range rather than a single MTD
• Incorporating randomization in dose escalation trials to minimize bias
• Allowing flexibility in trial designs, including intrapatient dose escalation when appropriate
• Considering multiple recommended doses for different disease contexts, molecular alterations, or tumor sites 1