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Understanding Maximum Dose in Therapeutic and Safety Contexts
Maximum Effective Dose (MaxED) in Therapeutic Drugs
The concept of the Maximum Effective Dose (MaxED) is crucial in determining the optimal dose of therapeutic drugs. MaxED is defined as the dose above which no further improvement in efficacy is observed. Two experimental designs, a single-stage and a two-stage design, have been proposed to select the MaxED among several fixed doses. The single-stage design involves selecting the MaxED and assessing its efficacy at the end of the experiment, while the two-stage design allows for an interim analysis to potentially stop the trial early if the treatment effect at MaxED is extreme. This approach uses isotonic regression under the restriction of monotonicity and applies Williams’ test to compare the selected MaxED with a control1.
Maximum Safe Dose (MAXSD) in Safety Assessments
Identifying the Maximum Safe Dose (MAXSD) is essential in both clinical dose-finding studies and toxicological studies. MAXSD is the highest dose that does not significantly increase safety risks compared to a placebo or control group. A multiple testing procedure for equivalence in a many-to-one design with a priori ordered contrasts has been proposed to identify MAXSD. This method prioritizes controlling the false-negative error rate over the false-positive rate, ensuring safety in dose recommendations2.
Maximum Recommended Doses of Local Anesthetics
The recommendations for maximum doses of local anesthetics are often not based on randomized controlled studies but rather on clinical experiences, animal experiments, and pharmacokinetic results. For instance, the maximum dose of lidocaine has been set at 200 mg due to the common occurrence of central nervous system toxicity at higher doses. Recommendations for local anesthetic doses should consider factors such as the site of injection, patient age, organ dysfunctions, and pregnancy. Additionally, the use of epinephrine can help manage the administration of large doses, provided there are no contraindications3.
Maximum Tolerated Dose (MTD) in Drug Development
The Maximum Tolerated Dose (MTD) is a key concept in drug development, particularly in Phase I trials. MTD is defined as the highest dose that does not cause unacceptable toxicity. Determining the MTD helps ensure that doses tested in subsequent trials are both safe and potentially efficacious. However, there is no consensus on the exact definition of MTD, leading to variability in its determination. MTD is typically identified as the dose that causes mild to moderate sublethal toxic effects in a significant percentage of individuals7 8.
Maximum Dose in Radiotherapy
In radiotherapy, particularly in the treatment of nonsmall cell lung cancer with stereotactic body radiotherapy (SBRT), the maximum biologically effective dose (maxBED) within the planning target volume (PTV) is a critical factor. Studies have shown that while there is no significant difference in local control rates between patients treated with maxBED below or above 120 Gy, a higher maxBED tends to improve local control rates, suggesting that a threshold greater than 120 Gy may be necessary for better outcomes10.
Conclusion
The determination of maximum doses, whether for efficacy, safety, or therapeutic purposes, is a complex process that involves various experimental designs and considerations. From the MaxED in therapeutic drugs to the MAXSD in safety assessments and the MTD in drug development, each context requires careful evaluation to balance efficacy and safety. Understanding these concepts and their applications is essential for optimizing drug dosing and improving patient outcomes.
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Statistical Methods for Selecting Maximum Effective Dose and Evaluating Treatment Effect When Dose–Response is Monotonic
The two-stage design enables earlier selection of the maximum effective dose and stopping the trial earlier if the treatment effect is extreme.
Non-RCTIDENTIFYING THE MAXIMUM SAFE DOSE: A MULTIPLE TESTING APPROACH
A multiple testing procedure with a priori ordered contrasts can effectively identify the maximum safe dose in safety assessment, reducing false-negative error rates.
Maximum Recommended Doses of Local Anesthetics: A Multifactorial Concept
Maximum local anesthetic doses should be individualized, based on patient factors and the site of injection, rather than exact milligram or mg/kg doses.
Highly CitedA rapid method to determine the maximum dose from parallel opposed fields.
The developed method allows rapid calculation of maximum dose from parallel opposed fields, with a calculating wheel designed for practical use.
The Myth of a Minimum Dose for Atropine
The minimum dose of atropine recommended by PALS is 0.1 mg, regardless of the child's body weight, and this dose may be potentially lethal if overdosing occurs.
Why maximum tolerated dose?
Prescriptions at maximum tolerated dose (MTD) may not improve outcomes and may lead to potential safety issues, with oral effective dose 50 (ED50) potentially being a useful guide for balancing efficacy and safety.
Rigorous JournalDefining the Maximum Tolerated Dose: Investigator, Academic, Industry and Regulatory Perspectives
The maximum tolerated dose (MTD) is crucial in drug development, ensuring safe and potentially efficacious dose ranges for efficacy trials.
Characterization of Dose Distributions Through the Max and Mean Dose Concept
The max & mean model effectively determines the equivalent uniform dose for inhomogeneously irradiated normal organs, providing useful predictions for planning intensity-modulated radiotherapy.
Impact of Maximum Point Dose Within the Planning Target Volume on Local Control of Nonsmall Cell Lung Cancer Treated With Stereotactic Body Radiotherapy
Higher maximum point doses in stereotactic body radiotherapy for early-stage nonsmall cell lung cancer may improve local control rates, but a threshold greater than 120 Gy may be needed for better outcomes.
Observational Study