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Determining the optimal dose size and dosing frequency in pharmacotherapy is crucial for achieving therapeutic effectiveness while minimizing adverse effects. This article explores the methodologies employed in determining these parameters, focusing on their significance and interplay to tailor dosing regimens.Dose Size: Dose size refers to the amount of a drug administered in a single dose. It is determined based on the drug's pharmacodynamics and pharmacokinetics properties and...
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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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A medication’s effectiveness largely depends on its appropriate dosage and the route of administration. Dosage ensures that a sufficient drug concentration is maintained in the bloodstream to elicit the desired therapeutic effect without causing toxicity. The route of administration affects the drug's bioavailability, rate of absorption, and onset of action, which are crucial for achieving optimal therapeutic outcomes. Drug dosage calculations are critical to tailoring therapy to...
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Gentamicin, an aminoglycoside antibiotic, is commonly administered via intermittent intravenous infusion to treat severe infections. An intermittent one-hour infusion of gentamicin, administered at eight-hour intervals, allows for precise control of plasma drug concentrations, minimizing toxicity while ensuring therapeutic efficacy. Pharmacokinetic principles govern the dynamics of plasma concentrations and can be mathematically described using specific equations.The plasma drug concentration...
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Agonists can bind with and activate receptors, resulting in the formation of drug-receptor complexes. Once formed, these complexes catalyze many biochemical processes at the cellular level and subsequently induce a pharmacologic response. The degree of response is directly proportional to the fraction of activated receptors, which in turn, depends on the concentration of the drug at the receptor site as well as the sensitivity of the receptor. An increase in the administered dose contributes to...
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Coherence principles in interval-based dose finding.

Nolan A Wages1, Alexia Iasonos2, John O'Quigley3

  • 1Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.

Pharmaceutical Statistics
|November 7, 2019
PubMed
Summary
This summary is machine-generated.

Interval-based dose-finding methods like Bayesian optimal interval and Keyboard are not coherent, leading to incorrect dose escalation or deescalation. These methods frequently make incoherent decisions, especially with small patient cohorts.

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Area of Science:

  • Clinical Trials
  • Biostatistics
  • Pharmacology

Background:

  • Dose-finding trials are crucial for determining optimal drug dosages.
  • Interval-based methods are commonly used but may have limitations.
  • Coherence is a desirable property for dose-finding decision-making.

Purpose of the Study:

  • To evaluate the coherence of interval-based dose-finding methods.
  • To identify and quantify incoherent decisions in simulated clinical trials.
  • To assess the impact of cohort size on method coherence.

Main Methods:

  • Simulated clinical trials with varying sample sizes and cohort sizes.
  • Analysis of dose-limiting toxicity outcomes.
  • Comparison of Bayesian optimal interval and Keyboard methods.
  • Calculation of incoherent decision rates and probabilities.

Main Results:

  • Both Bayesian optimal interval and Keyboard methods exhibited significant incoherence.
  • In simulations with cohort size 1, 36% of decisions were incoherent.
  • The probability of at least one incoherent decision per trial exceeded 75%.

Conclusions:

  • Interval-based dose-finding methods, particularly with small cohorts, violate the principle of coherence.
  • Modifications are needed to improve the coherency of these methods.
  • Researchers should carefully consider dose assignment behavior in interval-based methods.