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Optimal duration of therapy with trastuzumab
1Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
Abstract:
One of the primary objectives of early clinical drug development is to determine the optimal dose and schedule of administration of the drug under study. If this objective is accomplished, subsequent clinical trials can truly evaluate the antitumor efficacy, tolerability, and safety of the new drug, and the appropriate assessment of benefit/risk can be made. A full understanding of the mechanisms not only of antitumor activity but also of side effects and toxicity is critical to select the optimal schedule of administration. In this regard, preclinical (in vitro and in vivo) studies are often helpful before clinical studies are initiated. However, no preclinical model is fully predictive of the outcome of human clinical trials. Therefore, while preclinical studies can point to potentially fruitful directions in clinical investigation, only after fairly substantial clinical experience does the medical community reach agreement and understanding of the optimal dose and schedule of administration of an agent. For some agents, these conclusions are reached early in the development of the drug (eg, cyclophosphamide, docetaxel). For others (eg, fluorouracil, cytosine arabinoside) the definition of optimal dose and schedule of administration is a never-ending story. The optimal duration of administration for trastuzumab is not known and is currently under active investigation.
Insights
Determining the optimal drug dose and schedule is crucial for evaluating new cancer therapies. While preclinical studies guide this process, definitive answers often require extensive clinical experience and ongoing research for agents like trastuzumab.
Area of Science:
- Pharmacology
- Clinical Drug Development
- Oncology
Background:
- Optimal dosing and scheduling are critical objectives in early clinical drug development to accurately assess antitumor efficacy, tolerability, and safety.
- Understanding drug mechanisms, including antitumor activity and toxicity, is essential for selecting the best administration schedule.
- Preclinical studies (in vitro, in vivo) provide valuable guidance but do not fully predict human clinical trial outcomes.
Purpose of the Study:
- To highlight the importance of establishing optimal drug dosage and administration schedules in early clinical development.
- To discuss the role and limitations of preclinical models in predicting clinical outcomes.
- To emphasize that defining optimal drug administration often requires substantial clinical experience and can be an ongoing process.
Main Methods:
- Review of principles in early clinical drug development.
- Discussion of the utility and limitations of preclinical models.
- Analysis of historical examples of drug development (cyclophosphamide, docetaxel, fluorouracil, cytosine arabinoside).
Main Results:
- No preclinical model perfectly predicts human clinical trial results.
- Some drugs achieve consensus on optimal dosing/scheduling early (e.g., cyclophosphamide, docetaxel).
- For other drugs (e.g., fluorouracil, cytosine arabinoside), optimal dosing/scheduling remains under continuous investigation.
Conclusions:
- Establishing optimal drug dose and schedule is a complex process, often requiring extensive clinical data.
- Preclinical data are informative but insufficient for definitive determination of optimal clinical use.
- The optimal administration duration for trastuzumab is currently unknown and an active area of research.