title: The application of human phase 0 microdosing trials: A systematic review and perspectives.
abstract: A decreasing number of new therapeutic drugs reaching the clinic has led to the publication of regulatory guidelines on human microdosing trials by the European Medicines Agency in 2004 and the US Food and Drug Administration in 2006. Microdosing trials are defined by the administration of 1/100th of the therapeutic dose and designed to investigate basic drug properties. This review investigates the current application of phase 0 trials in medical research. Thirty-three studies found in PubMed and EMBASE were systematically reviewed for aim and analytical method. Pharmacokinetic studies have been a major focus of phase 0 trials, but drug distribution, drug-drug interactions, imaging and pharmacogenomics have also been investigated. Common analytical methods were tandem mass liquid chromatography, accelerator mass spectrometry and positron emission tomography. New ongoing trials are investigating the pharmacodynamics and chemoresistance of marketed drugs, suggesting that the application of phase 0 trials is still evolving.
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Svendsen
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.|b Department of Clinical Medicine , Aalborg University , Denmark.|c Clinical Cancer Research Center, Aalborg University Hospital , Denmark.
authors.forename: Tarec C
authors.initials: TC
authors.lastname: El-Galaly
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.|b Department of Clinical Medicine , Aalborg University , Denmark.|c Clinical Cancer Research Center, Aalborg University Hospital , Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkær
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.|b Department of Clinical Medicine , Aalborg University , Denmark.|c Clinical Cancer Research Center, Aalborg University Hospital , Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Bøgsted
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Laursen
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.|c Clinical Cancer Research Center, Aalborg University Hospital , Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmitz
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.
authors.forename: Paw
authors.initials: P
authors.lastname: Jensen
authors.affiliation: a Department of Hematology , Aalborg University Hospital , Denmark.|b Department of Clinical Medicine , Aalborg University , Denmark.|c Clinical Cancer Research Center, Aalborg University Hospital , Denmark.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Johnsen
mesh_terms: D001682:Biological Availability; D002853:Chromatography, Liquid; D002986:Clinical Trials as Topic / Q000331:legislation & jurisprudence / Q000379:methods; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005060:Europe; D006801:Humans; D055432:Metabolomics / Q000379:methods; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010597:Pharmacogenetics; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014481:United States
chemical_list: D004364:Pharmaceutical Preparations
keywords: Phase 0; dose linearity; human trials; microdosing; pharmacodynamics; pharmacokinetics