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Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment
AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no furth...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089614/ https://www.ncbi.nlm.nih.gov/pubmed/27121262 http://dx.doi.org/10.1111/bcp.12991 |
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author | Gupta, Neeraj Hanley, Michael J. Venkatakrishnan, Karthik Perez, Raymond Norris, Robin E. Nemunaitis, John Yang, Huyuan Qian, Mark G. Falchook, Gerald Labotka, Richard Fu, Siqing |
author_facet | Gupta, Neeraj Hanley, Michael J. Venkatakrishnan, Karthik Perez, Raymond Norris, Robin E. Nemunaitis, John Yang, Huyuan Qian, Mark G. Falchook, Gerald Labotka, Richard Fu, Siqing |
author_sort | Gupta, Neeraj |
collection | PubMed |
description | AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single‐dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28‐day cycles. RESULTS: Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics‐evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95–1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose‐normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug‐related adverse event; there were no drug‐related grade 4 adverse events. CONCLUSIONS: In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment. |
format | Online Article Text |
id | pubmed-5089614 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50896142016-11-09 Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment Gupta, Neeraj Hanley, Michael J. Venkatakrishnan, Karthik Perez, Raymond Norris, Robin E. Nemunaitis, John Yang, Huyuan Qian, Mark G. Falchook, Gerald Labotka, Richard Fu, Siqing Br J Clin Pharmacol Pharmacokinetics AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single‐dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28‐day cycles. RESULTS: Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics‐evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95–1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose‐normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug‐related adverse event; there were no drug‐related grade 4 adverse events. CONCLUSIONS: In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment. John Wiley and Sons Inc. 2016-05-29 2016-09 /pmc/articles/PMC5089614/ /pubmed/27121262 http://dx.doi.org/10.1111/bcp.12991 Text en © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Pharmacokinetics Gupta, Neeraj Hanley, Michael J. Venkatakrishnan, Karthik Perez, Raymond Norris, Robin E. Nemunaitis, John Yang, Huyuan Qian, Mark G. Falchook, Gerald Labotka, Richard Fu, Siqing Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment |
title | Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment |
title_full | Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment |
title_fullStr | Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment |
title_full_unstemmed | Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment |
title_short | Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment |
title_sort | pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment |
topic | Pharmacokinetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089614/ https://www.ncbi.nlm.nih.gov/pubmed/27121262 http://dx.doi.org/10.1111/bcp.12991 |
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