title: Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development.
abstract: Receptor occupancy (RO) assays are designed to quantify the binding of therapeutics to their targets on the cell surface and are frequently used to generate pharmacodynamic (PD) biomarker data in nonclinical and clinical studies of biopharmaceuticals. When combined with the pharmacokinetic (PK) profile, RO data can establish PKPD relationships, which are crucial for informing dose decisions. RO is commonly measured by flow cytometry on fresh blood specimens and is subject to numerous technical and logistical challenges. To ensure that reliable and high quality results are generated from RO assays, careful assay design, key reagent characterization, data normalization/reporting, and thorough planning for implementation are of critical importance during development. In this article, the authors share their experiences and perspectives in these areas and discuss challenges and potential solutions when developing and implementing a flow cytometry-based RO method in support of biopharmaceutical drug development.
authors.affiliation: Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043.
authors.forename: Meina
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwickart
authors.affiliation: Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Schneider
authors.affiliation: Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043.
authors.forename: Inna
authors.initials: I
authors.lastname: Vainshtein
authors.affiliation: Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043.
authors.forename: Christopher
authors.initials: C
authors.lastname: Del Nagro
authors.affiliation: Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043.
authors.forename: Nathan
authors.initials: N
authors.lastname: Standifer
authors.affiliation: Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043.
authors.forename: Lorin K
authors.initials: LK
authors.lastname: Roskos
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D055808:Drug Discovery; D005434:Flow Cytometry / Q000379:methods*; D006801:Humans; D010599:Pharmacokinetics
chemical_list: D015415:Biomarkers
keywords: PKPD relationship; animal and human studies; biopharmaceutical; clinical trial; dose selection; drug development; flow cytometry; pharmacodynamic biomarker; receptor occupancy; target binding