Abstract
Abstract
Purpose
Quantification of pharmacodynamic interactions is key in combination therapies, yet conventional checkerboard experiments with up to 10 by 10 combinations are labor-intensive. Therefore, this study provides optimized experimental rhombic checkerboard designs to enable an efficient interaction screening with significantly reduced experimental workload.
Methods
Based on the general pharmacodynamic interaction (GPDI) model implemented in Bliss Independence, a novel rhombic ‘dynamic’ checkerboard design with quantification of bacteria instead of turbidity as endpoint was developed. In stochastic simulations and estimations (SSE), the precision and accuracy of interaction parameter estimations and classification rates of conventional reference designs and the newly proposed rhombic designs based on effective concentrations (EC) were compared.
Results
Although a conventional rich design with 20-times as many combination scenarios provided estimates of interaction parameters with higher accuracy, precision and classification rates, the optimized rhombic designs with one natural growth scenario, three monotherapy scenarios per combination partner and only four combination scenarios were still superior to conventional reduced designs with twice as many combination scenarios. Additionally, the rhombic designs were able to identify whether an interaction occurred as a shift on maximum effect or EC50 with > 98%. Overall, effective concentration-based designs were found to be superior to traditional standard concentrations, but were more challenged by strong interaction sizes exceeding their adaptive concentration ranges.
Conclusion
The rhombic designs proposed in this study enable a reduction of resources and labor and can be a tool to streamline higher throughput in drug interaction screening.
Funder
Bundesministerium für Bildung und Forschung
Agence nationale de la recherche, France
Universität Hamburg
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Organic Chemistry,Pharmaceutical Science,Pharmacology,Molecular Medicine,Biotechnology
Cited by
1 articles.
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