title: Pharmaceutical quality control of the investigational polymer-conjugated platinum anticancer agent AP 5280.
abstract: AP 5280 is a novel polymer-conjugated platinum anticancer agent currently in Phase I clinical trials. In order to guarantee the quality of AP 5280 drug substance for use in the manufacture of a drug product for intravenous human use, an array of tests was utilized for its quality control. Proton nuclear magnetic resonance (1H NMR) spectroscopy and infrared (IR) spectroscopy were employed for structural identification. The molecular weight (MW) and MW distribution, which play a large role in the distribution of AP 5280 in vivo, were determined by Size Exclusion Chromatography (SEC). Platinum binding assessment was performed using platinum nuclear magnetic resonance (195Pt NMR) spectroscopy. The free platinum content and release profile of small platinum species, measured using Flameless Atomic Absorption Spectroscopy (F-AAS), were determined as a measure of molecular integrity, a very important aspect of its assumed mechanism of action. The total platinum content of the copolymer was determined employing flame Atomic Absorption Spectroscopy (AAS). The combined results of the analyses performed on AP 5280 drug substance provided a meaningful picture of its structure, size, and integrity--an excellent basis for its quality control.
authors.affiliation: Slotervaart Hospital/The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, 1066 EC Amsterdam, The Netherlands. M.Bouma@wza.nl
authors.forename: Marjan
authors.initials: M
authors.lastname: Bouma
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
authors.forename: Donald R
authors.initials: DR
authors.lastname: Stewart
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Shannon
authors.forename: John V
authors.initials: JV
authors.lastname: St John
authors.forename: John R
authors.initials: JR
authors.lastname: Rice
authors.forename: Remko
authors.initials: R
authors.lastname: Harms
authors.forename: Bart A J
authors.initials: BA
authors.lastname: Jansen
authors.forename: Steven
authors.initials: S
authors.lastname: van Zutphen
authors.forename: Jan
authors.initials: J
authors.lastname: Reedijk
authors.forename: Auke
authors.initials: A
authors.lastname: Bult
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D009944:Organoplatinum Compounds / Q000737:chemistry*; D011786:Quality Control; D013055:Spectrophotometry, Infrared; D013678:Technology, Pharmaceutical
chemical_list: D000178:Acrylamides; C438846:HPMA copolymer-platinate; D009944:Organoplatinum Compounds