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.
Investigational new drugs. 2016 May 25 [Epub ahead of print]
Cynthia M Nijenhuis, Edward Hellriegel, Jos H Beijnen, Diane Hershock, Alwin D R Huitema, Luc Lucas, Marja Mergui-Roelvink, Mihaela Munteanu, Laura Rabinovich-Guilatt, Philmore Robertson, Hilde Rosing, Ofer Spiegelstein, Jan H M Schellens
Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands., Teva Branded Pharmaceutical Products R&D, Nonclinical DMPK, West Chester, PA, USA., Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands., Teva Branded Pharmaceutical Products R&D, Oncology Clinical Development, Frazer, PA, USA., Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands., Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands., Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Teva Branded Pharmaceutical Products R&D, Oncology Clinical Development, Frazer, PA, USA., Teva Global Branded Products, 41 Moores Road, PO Box 4011, Frazer, PA, 19355, USA. ., Teva Branded Pharmaceutical Products R&D, Nonclinical DMPK, West Chester, PA, USA., Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands., Teva Global Branded Products, Netanya, Israel., Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.