title: Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in plasma of patients in a Phase I study.
abstract: E-3-(4'-Hydroxy-3'-adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel oral synthetic adamantyl retinoid derivative, now under early clinical investigation in patients with ovarian cancer. To investigate the pharmacokinetics of this new antitumor agent in human plasma, we developed and validated a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method based on the addition of ST2222 as internal standard and simple protein precipitation with methanol. The method requires a small volume of sample (100microL); it is rapid and selective, allowing a good resolution of peaks from the plasma matrix in 9min. The method offers high recovery (>90%), it is sensitive, precise and accurate with overall precision expressed as CV% less than 8.2%. We set the lower limit of quantitation at 20.0ng/mL and validated the assay up to the concentration of 1000.0ng/mL. The present method has been successfully applied to study ST1926 pharmacokinetics in patients with advanced ovarian cancer in a Phase I trial, administering the drug orally for five consecutive days. During analysis of the study samples, it became evident the presence of glucuroconjugates of the parent compound, established by LC-Orbitrap MS. Preliminary results show low and variable drug absorption in patients, with extensive glucuroconjugation influencing the bioavailability of ST1926.
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Sala
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.forename: Renzo
authors.initials: R
authors.lastname: Bagnati
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Silvia
authors.initials: S
authors.lastname: Pace
authors.forename: Francesca
authors.initials: F
authors.lastname: Capocasa
authors.forename: Elena
authors.initials: E
authors.lastname: Marangon
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000097:blood* / Q000627:therapeutic use; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D002934:Cinnamates / Q000097:blood* / Q000627:therapeutic use; D004355:Drug Stability; D005260:Female; D006801:Humans; D016014:Linear Models; D010051:Ovarian Neoplasms / Q000097:blood* / Q000188:drug therapy; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; D000218:Adamantane