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Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.
Meng, Teng; Jung, Donald; Cai, Xiao-Hong; Lu, Zhao-Qiang; Yu, Ji-Bing; Qi, Tian-Yang; Meng, Fan-Ying; Ruan, Mei-Zhen; Duan, Jian-Xin.
Afiliação
  • Meng T; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Jung D; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Cai XH; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Lu ZQ; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Yu JB; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Qi TY; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Meng FY; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Ruan MZ; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
  • Duan JX; Ascentawits Pharmaceuticals, Ltd, Shenzhen, China.
Biopharm Drug Dispos ; 45(2): 83-92, 2024 Apr.
Article em En | MEDLINE | ID: mdl-38492211
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pró-Fármacos / Compostos de Mostarda Nitrogenada Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pró-Fármacos / Compostos de Mostarda Nitrogenada Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article