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The AAPS Journal

, 21:95 | Cite as

Optimizing Dose-Finding Studies for Drug Combinations Based on Exposure-Response Models

  • Theodoros PapathanasiouEmail author
  • Anders Strathe
  • Rune Viig Overgaard
  • Trine Meldgaard Lund
  • Andrew C. Hooker
Research Article

Abstract

Combinations of pharmacological treatments are increasingly being investigated for potentially higher clinical benefit, especially when the combined drugs are expected to act via synergistic interactions. The clinical development of combination treatments is particularly challenging, particularly during the dose-selection phase, where a vast range of possible combination doses exists. The purpose of this work was to evaluate the added value of using optimal design for guiding the dose allocation in drug combination dose-finding studies as compared with a typical drug-combination trial. Optimizations were performed using local [D(s)-optimality] and global [ED(s)-optimality] optimal designs to maximize the precision of model parameters in a number of potential exposure-response (E-R) surfaces. A compound criterion [D(s)/V-optimality] was used to optimize the precision of model predictions in specific parts of the E-R surfaces. Optimal designs provided unbiased estimates and significantly improved the accuracy of results relative to the typical design. It was possible to improve the efficiency and overall parameter precision up to 7832% and 96.6% respectively. When the compound criterion was used, the probability to accurately identify the optimal dose-combination increased from 71% for the typical design up to 91%. These results indicate that optimal design methodology in tandem with E-R analyses is a beneficial tool that can be used for appropriate dose allocation in dose-finding studies for drug combinations.

Key Words

Dose allocation Drug combinations Exposure-response analyses Optimal design Response surface 

Notes

Funding Information

This work was financially supported by the Novo Nordisk STAR Fellowship Programme and the Innovation Fund Denmark.

Supplementary material

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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Theodoros Papathanasiou
    • 1
    • 2
    Email author
  • Anders Strathe
    • 2
  • Rune Viig Overgaard
    • 2
  • Trine Meldgaard Lund
    • 1
  • Andrew C. Hooker
    • 3
  1. 1.Department of Drug Design and Pharmacology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.Novo Nordisk A/S, Quantitative Clinical PharmacologySøborgDenmark
  3. 3.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden

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