Back to Search
Start Over
Found in Translation: Maximizing the Clinical Relevance of Nonclinical Oncology Studies
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 23(4)
- Publication Year :
- 2016
-
Abstract
- Purpose: The translation of nonclinical oncology studies is a subject of continuous debate. We propose that translational oncology studies need to optimize both pharmacokinetic (drug exposure) and pharmacodynamic (xenograft model) aspects. While improvements in pharmacodynamic translatability can be obtained by choosing cell lines or patient-derived xenograft models closer to the clinical indication, significant ambiguity and variability exists when optimizing the pharmacokinetic translation of small molecule and biotherapeutic agents. Experimental Design and Results: In this work, we propose a pharmacokinetic-based strategy to select nonclinical doses for approved drug molecules. We define a clinically relevant dose (CRD) as the dosing regimen in mice that most closely approximates the relevant pharmacokinetic metric in humans. Such metrics include area under the time–concentration curve and maximal or minimal concentrations within the dosing interval. The methodology is applied to six drugs, including targeted agents and chemotherapeutics, small and large molecules (erlotinib, dasatinib, vismodegib, trastuzumab, irinotecan, and capecitabine). The resulting efficacy response at the CRD is compared with clinical responses. Conclusions: We conclude that nonclinical studies designed with the appropriate CRDs of approved drug molecules will maximize the translatability of efficacy results, which is critical when testing approved and investigational agents in combination. Clin Cancer Res; 23(4); 1080–90. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Vismodegib
Medical Oncology
Approved drug
Capecitabine
Small Molecule Libraries
Translational Research, Biomedical
03 medical and health sciences
Mice
0302 clinical medicine
Pharmacokinetics
Trastuzumab
Internal medicine
Neoplasms
Medicine
Animals
Humans
Dose-Response Relationship, Drug
business.industry
Xenograft Model Antitumor Assays
Irinotecan
030104 developmental biology
030220 oncology & carcinogenesis
Pharmacodynamics
Erlotinib
business
medicine.drug
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 23
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....7611fccb595167ac83e66ec8e661c334