Biotransformation of [14C]-ixazomib in patients with advanced solid tumors : characterization of metabolite profiles in plasma, urine, and feces
PURPOSE: This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-ixazomib.
METHODS: After administration of a single 4.1-mg oral dose of [14C]-ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0-168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry.
RESULTS: Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0-816 h time-proportional pooled plasma, ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0-35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active.
CONCLUSIONS: Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of ixazomib. The inference of formation-rate-limited clearance of ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:82 |
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| Enthalten in: |
Cancer chemotherapy and pharmacology - 82(2018), 5 vom: 20. Nov., Seite 803-814 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pusalkar, Sandeepraj [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.08.2019 Date Revised 26.08.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00280-018-3671-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM287675173 |
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| 041 | |a eng | ||
| 100 | 1 | |a Pusalkar, Sandeepraj |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Biotransformation of [14C]-ixazomib in patients with advanced solid tumors |b characterization of metabolite profiles in plasma, urine, and feces |
| 264 | 1 | |c 2018 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.08.2019 | ||
| 500 | |a Date Revised 26.08.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-ixazomib | ||
| 520 | |a METHODS: After administration of a single 4.1-mg oral dose of [14C]-ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0-168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry | ||
| 520 | |a RESULTS: Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0-816 h time-proportional pooled plasma, ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0-35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active | ||
| 520 | |a CONCLUSIONS: Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of ixazomib. The inference of formation-rate-limited clearance of ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Accelerator mass spectrometry | |
| 650 | 4 | |a Biotransformation | |
| 650 | 4 | |a Boronic acid | |
| 650 | 4 | |a Ixazomib | |
| 650 | 4 | |a Phase I | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Boron Compounds |2 NLM | |
| 650 | 7 | |a Carbon Radioisotopes |2 NLM | |
| 650 | 7 | |a ixazomib |2 NLM | |
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| 650 | 7 | |a Glycine |2 NLM | |
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| 700 | 1 | |a Plesescu, Mihaela |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Neeraj |e verfasserin |4 aut | |
| 700 | 1 | |a Hanley, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Venkatakrishnan, Karthik |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jing-Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Cindy |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaoquan |e verfasserin |4 aut | |
| 700 | 1 | |a Chowdhury, Swapan |e verfasserin |4 aut | |
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