title: Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors.
abstract: Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Nijenhuis
authors.affiliation: Teva Branded Pharmaceutical Products R&D, Nonclinical DMPK, West Chester, PA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Hellriegel
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Teva Branded Pharmaceutical Products R&D, Oncology Clinical Development, Frazer, PA, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Hershock
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.
authors.forename: Luc
authors.initials: L
authors.lastname: Lucas
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marja
authors.initials: M
authors.lastname: Mergui-Roelvink
authors.affiliation: Teva Branded Pharmaceutical Products R&D, Oncology Clinical Development, Frazer, PA, USA.|ImmunoGen, Inc, Waltham, MA, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Munteanu
authors.affiliation: Teva Global Branded Products, 41 Moores Road, PO Box 4011, Frazer, PA, 19355, USA. laura.rabinovich@tevapharm.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Rabinovich-Guilatt
authors.affiliation: Teva Branded Pharmaceutical Products R&D, Nonclinical DMPK, West Chester, PA, USA.
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Teva Global Branded Products, Netanya, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D005260:Female; D006248:Harringtonines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000077863:Homoharringtonine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: C578464:4'-desmethylhomoharringtonine; D000972:Antineoplastic Agents, Phytogenic; D002250:Carbon Radioisotopes; D006248:Harringtonines; D000077863:Homoharringtonine
keywords: Excretion; Mass balance; Metabolism; Omacetaxine mepesuccinate; Pharmacokinetics