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Design and Sample Size for Evaluating Combinations of Drugs of Linear and Loglinear Dose-Response Curves

Authors: Fang, HB; Tian, GL; Tan, M; Li, W;

Design and Sample Size for Evaluating Combinations of Drugs of Linear and Loglinear Dose-Response Curves

Abstract

The study of drug combinations has become important in drug development due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. The goal is to identify which combinations are additive, synergistic, or antagonistic. Although there exists statistical framework for finding doses and sample sizes needed to detect departure from additivity, e.g., the power maximized F-test, different classes of drugs of different does-response shapes require different derivation for calculating sample size and finding doses. Motivated by two anticancer combination studies that we are involved with, this article proposes dose-finding and sample size method for detecting departures from additivity of two drugs with linear and log-linear single dose-response curves. The first study involves combination of two drugs, where one single drug dose-response curve is linear and the other is log-linear. The second study involves combinations of drugs whose single drug dose-response curves are linear. The experiment had been planned with the common fixed ratio design before we were consulted, but the resulting data missed the synergistic combinations. However, the experiment based on the proposed design was able to identify the synergistic combinations as anticipated. Thus we shall summarize the analysis of the data collected according to the proposed design and discuss why the commonly used fixed ratio method failed and the implications of the proposed method for other combination studies.

Country
China (People's Republic of)
Keywords

Data Interpretation, Cell Survival, Cell Survival - Drug Effects, Antineoplastic Agents, 310, Cell Line, Dose-Response Relationship, Research Design - Statistics & Numerical Data, Models, Cell Line, Tumor, Analysis Of Variance, Humans, Analysis of Variance, Tumor, Models, Statistical, Dose-Response Relationship, Drug, Antineoplastic Agents - Pharmacology - Toxicity, Drug Synergism, Statistical, Research Design, Data Interpretation, Statistical, Sample Size, Linear Models, Drug

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
7
Average
Average
Average
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