Characterization of AST-001 non-clinical pharmacokinetics : A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys
© 2024 Ascentawits Pharmaceuticals,LTD. Biopharmaceutics & Drug Disposition published by John Wiley & Sons Ltd..
AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:45 |
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| Enthalten in: |
Biopharmaceutics & drug disposition - 45(2024), 2 vom: 16. Apr., Seite 83-92 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meng, Teng [VerfasserIn] |
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| Links: |
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| Themen: |
AKR1C3 |
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| Anmerkungen: |
Date Completed 19.04.2024 Date Revised 19.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/bdd.2385 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369818873 |
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| 520 | |a © 2024 Ascentawits Pharmaceuticals,LTD. Biopharmaceutics & Drug Disposition published by John Wiley & Sons Ltd. | ||
| 520 | |a AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AKR1C3 | |
| 650 | 4 | |a AST‐001 | |
| 650 | 4 | |a AST‐2660 | |
| 650 | 4 | |a pharmacokinetics | |
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| 700 | 1 | |a Jung, Donald |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Xiao-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Zhao-Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Ji-Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Tian-Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Fan-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Ruan, Mei-Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Duan, Jian-Xin |e verfasserin |4 aut | |
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