title: Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies.
abstract: Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitroorin vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose-response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection ofin vitroconcentrations andin vivoplasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects.Clin Cancer Res; 23(14); 3489-98. ©2017 AACR.
authors.affiliation: Division of Cancer Treatment and Diagnosis, Developmental Therapeutics Program, Toxicology and Pharmacology Branch, National Cancer Institute, Bethesda, Maryland. dane.liston@nih.gov.
authors.forename: Dane R
authors.initials: DR
authors.lastname: Liston
authors.affiliation: Division of Cancer Treatment and Diagnosis, Developmental Therapeutics Program, Toxicology and Pharmacology Branch, National Cancer Institute, Bethesda, Maryland.
authors.forename: Myrtle
authors.initials: M
authors.lastname: Davis
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008495:Medical Oncology / Q000639:trends*; D009369:Neoplasms / Q000188:drug therapy*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents