title: Is sunitinib a Narrow Therapeutic Index Drug? - A systematic review and in vitro toxicology-analysis of Sunitinib vs. Imatinib in cells from different tissues.
abstract: Narrow Therapeutic Index Drugs (NTIDs) are characterized by a small range between therapeutic and toxicological effect. Missing international harmonized definition for NTIDs the EMA does not even have a definition of NTIDs in contrast to the U.S. FDA, Health Canada, and the Japanese NIHS. Sunitinib, a tyrosine kinase inhibitor (TKI), indicated for the treatment of certain cancer types, will be running off-patent soon. Falling into the category of NTID would have a major impact on regulatory requirements for generic applications. Our analyses of metadata revealed numerous arguments in favor of a NTID designation. We used in vitro experiments to also give initial experimental answers. Five cell types of different tissue origin were examined for determination of IC50-values in cell viability assays. For comparison, the first-in-class TKI Imatinib was used as reference non-NTID drug. In addition, apoptotic proteins were investigated with respect to their expression and phosphorylation status. These in vitro experiments showed systematically higher toxicity of Sunitinib compared to Imatinib and a different expression and phosphorylation pattern of apoptotic proteins. In vitro data can only give preliminary results and further experiments with clinical blood samples and tumor biopsies are needed to finally clarify NTID status of Sunitinib.
authors.affiliation: Federal Institute of Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany. Electronic address: bodo.haas@bfarm.de.
authors.forename: Bodo
authors.initials: B
authors.lastname: Haas
authors.affiliation: Federal Institute of Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Weber-Lassalle
authors.affiliation: Federal Institute of Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Frötschl
authors.affiliation: Federal Institute of Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany; Applied Pharmacy, University of Applied Sciences Kaiserslautern, Campus Pirmasens, Carl-Schurz-Str. 10-16, 66953 Pirmasens, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Eckstein
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004335:Drug and Narcotic Control; D016568:Drugs, Generic / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000633:toxicity*; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity*; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D011758:Pyrroles / Q000008:administration & dosage / Q000633:toxicity*; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D016568:Drugs, Generic; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000068877:Imatinib Mesylate; D000077210:Sunitinib
keywords: Apoptosis; Cell viability; Drug safety; Imatinib; Narrow Therapeutic Index Drug (NTID); Receptor tyrosine kinase (RTK); Sunitinib; Toxicity; Tyrosine kinase inhibitor (TKI)