title: Pharmacokinetics and excretion of14C-Plitidepsin in patients with advanced cancer.
abstract: Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. In total, a mean of 77.4% of the administered radioactivity was excreted over a time period of 20 days, of which 71.3% was recovered in faeces and 6.1% was found in urine. The majority excreted in urine was accounted for by unchanged plitidepsin, with only 1.5% of the total administered dose explained by metabolites in urine. Faeces, on the other hand contained low levels of parent compound, which means that most of the TRA excreted in faeces was accounted for by metabolites. TRA levels were 3.7 times higher in whole blood compared to plasma. Plitidepsin was widely distributed and plasma clearance was low. This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion.
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek / The Netherlands Cancer Institute, P.O. Box 90440, 1006, BK, Amsterdam, The Netherlands. l.v.andel@nki.nl.
authors.forename: L
authors.initials: L
authors.lastname: van Andel
authors.affiliation: Pharma Mar, S.A. Colmenar Viejo, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Fudio
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek / The Netherlands Cancer Institute, P.O. Box 90440, 1006, BK, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Pharma Mar, S.A. Colmenar Viejo, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Munt
authors.affiliation: Pharma Mar, S.A. Colmenar Viejo, Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Miguel-Lillo
authors.affiliation: Pharma Mar, S.A. Colmenar Viejo, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: González
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek / The Netherlands Cancer Institute, P.O. Box 90440, 1006, BK, Amsterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Tibben
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek / The Netherlands Cancer Institute, P.O. Box 90440, 1006, BK, Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: de Vries
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek / The Netherlands Cancer Institute, P.O. Box 90440, 1006, BK, Amsterdam, The Netherlands.
authors.forename: A H M
authors.initials: AHM
authors.lastname: de Vries Schultink
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek / The Netherlands Cancer Institute, P.O. Box 90440, 1006, BK, Amsterdam, The Netherlands.|Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000284:Administration, Oral; D000368:Aged; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D047630:Depsipeptides / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D010456:Peptides, Cyclic; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D047630:Depsipeptides; D010456:Peptides, Cyclic; C000615234:Carbon-14; C098980:plitidepsin
keywords: ADME; Aplidin; LC-MS/MS; Mass balance; Pharmacokinetics; Plitidepsin; Total radioactivity