A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors
This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.Trial ID: ClinicalTrials.gov # NCT01953783.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Investigational new drugs - 36(2018), 3 vom: 05. Juni, Seite 407-415 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gupta, Neeraj [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.02.2019 Date Revised 25.02.2019 published: Print-Electronic ClinicalTrials.gov: NCT01953783 Citation Status MEDLINE |
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| doi: |
10.1007/s10637-017-0509-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM27603340X |
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| 100 | 1 | |a Gupta, Neeraj |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 25.02.2019 | ||
| 500 | |a Date Revised 25.02.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT01953783 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.Trial ID: ClinicalTrials.gov # NCT01953783 | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
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| 700 | 1 | |a Zhang, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Pusalkar, Sandeepraj |e verfasserin |4 aut | |
| 700 | 1 | |a Plesescu, Mihaela |e verfasserin |4 aut | |
| 700 | 1 | |a Chowdhury, Swapan |e verfasserin |4 aut | |
| 700 | 1 | |a Hanley, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Bingxia |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 Venkatakrishnan, Karthik |e verfasserin |4 aut | |
| 700 | 1 | |a Shepard, Dale R |e verfasserin |4 aut | |
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