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The correlation between a drug's dosage and its impact on a biological system is a cornerstone of pharmacology and toxicology. Conventional dose–response curves, which include graded and quantal relationships, are key to this understanding. Graded dose–response curves depict the spectrum of a biological reaction to different doses within an individual, indicating that as the drug dosage increases, so does the intensity of the response. On the other hand, quantal dose–response...
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A loading dose is an essential pharmacological strategy to rapidly achieve the target plasma drug concentration necessary for an immediate therapeutic effect. This approach is especially critical for drugs characterized by slow absorption or extended half-lives, where delaying therapeutic plasma levels could compromise treatment outcomes. By administering a loading dose, clinicians ensure a prompt onset of drug action, even for agents with complex pharmacokinetic profiles.Achieving steady-state...
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Dose-finding designs for cumulative toxicities using multiple constraints.

Shing M Lee1, Moreno Ursino2, Ying Kuen Cheung1

  • 1Department of Biostatistics, Mailman School of Public Health, Columbia University, 722 W. 168th St, New York, NY, USA.

Biostatistics (Oxford, England)
|November 16, 2017
PubMed
Summary
This summary is machine-generated.

This study introduces a new method to better determine the maximum tolerated dose (MTD) in cancer trials by considering both severe dose-limiting toxicities (DLT) and moderate toxicities. This approach improves safety by preventing recommendations of overly toxic doses.

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Area of Science:

  • Clinical Trials
  • Biostatistics
  • Pharmacology

Background:

  • Late-onset dose-limiting toxicities (DLT) and moderate toxicities are often overlooked in dose-finding cancer trials when determining the maximum tolerated dose (MTD).
  • Existing methods may not adequately account for cumulative or moderate toxicities that can lead to treatment discontinuation.

Purpose of the Study:

  • To propose an extension of the Time-to-Event Continual Reassessment Method (TITE-CRM) that incorporates constraints for both DLT and moderate toxicities.
  • To address the ad hoc handling of late-onset and cumulative toxicities in MTD determination.
  • To improve the safety and accuracy of dose selection in early-phase cancer clinical trials.

Main Methods:

  • An enhanced Time-to-Event Continual Reassessment Method (TITE-CRM) was developed to include toxicity constraints for both dose-limiting toxicities (DLT) and moderate toxicities.
  • The extended method accounts for partial information and late-onset toxicities.
  • The method was applied to an Erlotinib dose-finding trial with a notable incidence of moderate toxicities.

Main Results:

  • Simulations demonstrated that the proposed method effectively identifies dose levels that satisfy constraints for both DLT and moderate toxicities.
  • The method showed comparable correct selection probabilities to TITE-CRM when MTDs based on DLT and moderate toxicities align.
  • The enhanced method significantly reduces the likelihood of recommending a dose exceeding the true MTD.

Conclusions:

  • The proposed TITE-CRM extension provides a more robust framework for MTD determination in cancer trials by integrating moderate toxicity data.
  • This approach enhances patient safety by more accurately identifying safe and effective dose levels, particularly in trials with significant late-onset or moderate toxicities.
  • The method offers improved precision in dose selection compared to traditional approaches that primarily focus on DLTs.