title: Found in Translation: Maximizing the Clinical Relevance of Nonclinical Oncology Studies.
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.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism - New Biological Entities, Pfizer Worldwide Research and Development, San Diego, California. Mary.Spilker@pfizer.com.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Spilker
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism - New Biological Entities, Pfizer Worldwide Research and Development, San Diego, California.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism - New Biological Entities, Pfizer Worldwide Research and Development, San Diego, California.
authors.forename: Ravi
authors.initials: R
authors.lastname: Visswanathan
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism - New Biological Entities, Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Chandra
authors.initials: C
authors.lastname: Vage
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism - New Biological Entities, Pfizer Worldwide Research and Development, San Diego, California.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.affiliation: Global DMPK, Takeda California, San Diego, California.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism - New Biological Entities, Pfizer Worldwide Research and Development, San Diego, California.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vicini
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008495:Medical Oncology / Q000639:trends; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D054852:Small Molecule Libraries / Q000493:pharmacokinetics* / Q000627:therapeutic use; D057170:Translational Research, Biomedical / Q000639:trends; D023041:Xenograft Model Antitumor Assays
chemical_list: D054852:Small Molecule Libraries