title: A phase I open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors.
abstract: Cabazitaxel is a semisynthetic taxane approved for the treatment of patients with hormone-refractory metastatic prostate cancer (now known as metastatic castration-resistant prostate cancer) treated previously with a docetaxel-containing treatment regimen. The human plasma pharmacokinetics of cabazitaxel have been described previously, but detailed analyses of the metabolism and excretion pathways of cabazitaxel have not yet been published. Metabolite profiling, quantification, and identification as well as excretion analyses were carried out on samples from patients with advanced solid tumors who received an intravenous infusion of 25 mg/m [C]-cabazitaxel (50 μCi, 1.85 MBq) over 1 h. In plasma, cabazitaxel was the main circulating compound. Seven metabolites were detected, but with each accounting for 5% or less of the parent drug exposure, none were considered relevant metabolites. In excreta, 76.0% of the administered dose was recovered in feces within 2 weeks and 3.7% of the dose was excreted in urine within 1 week. Approximately 20 metabolites were detected in excreta; the main metabolites corresponded to combined mono-O-demethyl or di-O-demethyl derivatives on the taxane ring, with hydroxyl or cyclized derivatives on the lateral chain. Docetaxel (di-O-demethyl-cabazitaxel) was only detected at trace levels in excreta. These results suggest an extensive hepatic metabolism and biliary excretion of cabazitaxel in humans.
authors.affiliation: aSanofi R&D, Chilly-Mazarin bSanofi R&D, Vitry-sur-Seine, France cSanofi R&D, Cambridge, Massachusetts, USA dCharles River Biopharmaceutical Services, Tranent eEdinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ridoux
authors.forename: Dorothée R
authors.initials: DR
authors.lastname: Sémiond
authors.forename: Carine
authors.initials: C
authors.lastname: Vincent
authors.forename: Hélène
authors.initials: H
authors.lastname: Fontaine
authors.forename: Christine
authors.initials: C
authors.lastname: Mauriac
authors.forename: Ger-Jan
authors.initials: GJ
authors.lastname: Sanderink
authors.forename: Corina
authors.initials: C
authors.lastname: Oprea
authors.forename: Lindsay
authors.initials: L
authors.lastname: Kelly
authors.forename: Sally
authors.initials: S
authors.lastname: Clive
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004938:Esophageal Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy; D012983:Soft Tissue Neoplasms / Q000188:drug therapy; D043823:Taxoids / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D043823:Taxoids; C552428:cabazitaxel