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Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors

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 stud...

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Autores principales: Nijenhuis, Cynthia M., Hellriegel, Edward, Beijnen, Jos H., Hershock, Diane, Huitema, Alwin D. R., Lucas, Luc, Mergui-Roelvink, Marja, Munteanu, Mihaela, Rabinovich-Guilatt, Laura, Robertson, Philmore, Rosing, Hilde, Spiegelstein, Ofer, Schellens, Jan H. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007276/
https://www.ncbi.nlm.nih.gov/pubmed/27221729
http://dx.doi.org/10.1007/s10637-016-0360-9
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author Nijenhuis, Cynthia M.
Hellriegel, Edward
Beijnen, Jos H.
Hershock, Diane
Huitema, Alwin D. R.
Lucas, Luc
Mergui-Roelvink, Marja
Munteanu, Mihaela
Rabinovich-Guilatt, Laura
Robertson, Philmore
Rosing, Hilde
Spiegelstein, Ofer
Schellens, Jan H. M.
author_facet Nijenhuis, Cynthia M.
Hellriegel, Edward
Beijnen, Jos H.
Hershock, Diane
Huitema, Alwin D. R.
Lucas, Luc
Mergui-Roelvink, Marja
Munteanu, Mihaela
Rabinovich-Guilatt, Laura
Robertson, Philmore
Rosing, Hilde
Spiegelstein, Ofer
Schellens, Jan H. M.
author_sort Nijenhuis, Cynthia M.
collection PubMed
description 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.
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spelling pubmed-50072762016-09-16 Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors Nijenhuis, Cynthia M. Hellriegel, Edward Beijnen, Jos H. Hershock, Diane Huitema, Alwin D. R. Lucas, Luc Mergui-Roelvink, Marja Munteanu, Mihaela Rabinovich-Guilatt, Laura Robertson, Philmore Rosing, Hilde Spiegelstein, Ofer Schellens, Jan H. M. Invest New Drugs Phase I Studies 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. Springer US 2016-05-25 2016 /pmc/articles/PMC5007276/ /pubmed/27221729 http://dx.doi.org/10.1007/s10637-016-0360-9 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Phase I Studies
Nijenhuis, Cynthia M.
Hellriegel, Edward
Beijnen, Jos H.
Hershock, Diane
Huitema, Alwin D. R.
Lucas, Luc
Mergui-Roelvink, Marja
Munteanu, Mihaela
Rabinovich-Guilatt, Laura
Robertson, Philmore
Rosing, Hilde
Spiegelstein, Ofer
Schellens, Jan H. M.
Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors
title Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors
title_full Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors
title_fullStr Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors
title_full_unstemmed Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors
title_short Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors
title_sort pharmacokinetics and excretion of (14)c-omacetaxine in patients with advanced solid tumors
topic Phase I Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007276/
https://www.ncbi.nlm.nih.gov/pubmed/27221729
http://dx.doi.org/10.1007/s10637-016-0360-9
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