Abstract 749: A Phase I, open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors
Authors: Laurence Ridoux, Dorothée Semiond, Carine Vincent, Hélène Fontaine, Christine Mauriac, Gerard Sanderink, Corina Oprea, Sally Clive
Journal: Cancer Research (2012)

Abstract Background Cabazitaxel (Cbz) is a novel semi-synthetic taxane that promotes the assembly of tubulin and stabilizes microtubules. In preclinical studies, Cbz demonstrated efficacy in both docetaxel-sensitive and -resistant tumor models (Bissery et al. AACR 2000). Furthermore, the Phase III TROPIC trial demonstrated that, compared with mitoxantrone, Cbz improved overall survival in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen (hazard ratio 0.70; P &amp;lt; 0.0001). The human plasma pharmacokinetics of Cbz have been described previously (Mita et al. Clin Cancer Res 2009), but detailed analyses of the metabolism and excretion pathways of Cbz have not yet been published in the literature. Methods Four patients with advanced solid tumors (3 males; median age 52.5 years; performance status 0-1) received an IV infusion of 25 mg/m*2 [14C]-Cbz (50 µCi, 1.85 MBq) over 1 hour at cycle 1. Blood, plasma, urine, feces and expired air samples were collected at various times up to 14 days post-dosing. Radioactivity determination was performed by liquid scintillation counting, either directly (plasma, urine or CO2 traps) or after combustion (whole blood and feces). Analyses were carried out using liquid chromatography, with radioactivity and mass spectrometry detection for metabolite profiling, quantification and identification. Subsequent IV infusions were conducted every 3 weeks with non-radiolabeled drug until disease progression, intolerance or other study discontinuation criteria were reached. Results In plasma, Cbz was the main circulating compound, representing approximately 70% of the radioactivity AUC. Seven metabolites were detected, each accounting for ≤ 5% of the parent drug exposure; none of these, including the pharmacologically active docetaxel (di-O-demethyl-Cbz), were therefore considered relevant metabolites. In excreta, the majority of the radioactivity was recovered in feces (mean: 76.0% of administered dose within 2 weeks); 3.7% of the dose was excreted in urine within 1 week. No unchanged compound was excreted in feces and, on average, only 2.3% of the dose in urine, revealing an extensive hepatic metabolism of Cbz in humans. Approximately 20 metabolites were detected in excreta; the main metabolites corresponded to combined mono- 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 as traces in excreta. Conclusions Cbz is extensively metabolized in patients, but no relevant metabolites were observed in plasma, indicating that parent Cbz is the only entity responsible for the pharmacologic activity. Cbz metabolites are formed through 3 main metabolic pathways and are almost exclusively excreted in the feces. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 749. doi:1538-7445.AM2012-749