[Phase I clinical study of antineoplastic agents]

Area of Science:

• Pharmacology
• Toxicology
• Clinical Trials

Context:

• Current Phase I clinical trial dosing is empirical, often starting at 1/10th of the maximum tolerated dose (MTD).
• New drug candidates present challenges, with some requiring extensive dose escalation and others exceeding initial safety limits.
• Existing preclinical methods may not accurately predict human responses due to interspecies differences in ADME and target organ sensitivity.

Purpose:

• To highlight the limitations of current empirical dosing in early-phase clinical trials.
• To emphasize the need for advanced preclinical studies, including pharmacokinetic analysis and tissue enzyme assays.
• To propose improved strategies for determining safe and effective initial doses for novel therapeutic agents.

Summary:

• Phase I studies often rely on empirical dosing (e.g., 1/10th MELD10), which is insufficient for novel agents.
• Differences in Absorption, Distribution, Metabolism, and Excretion (ADME) between animals and humans necessitate pharmacokinetic studies.
• Variations in target organ sensitivity require tissue enzyme activity assays to establish MTD.
• Plasma peak level toxicity can be mitigated by using continuous infusion instead of IV bolus injection in preclinical studies.
• Novel agents may exhibit specific toxicities (neuro, hepato, cardiac) beyond bone marrow, demanding tailored preclinical evaluation.

Impact:

• Implementing pharmacokinetic studies and tissue enzyme assays can refine MTD determination for new drugs.
• Optimized preclinical strategies, including continuous infusion, will improve the safety and efficiency of early-phase clinical trials.
• This approach will accelerate the development of safer and more effective therapeutics by better predicting human responses and mitigating potential toxicities.