<br>健康受试者单次和多次口服剂量 Pritelivir 后的质量平衡和代谢特征,Clinical Pharmacology in Drug Development

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健康受试者单次和多次口服剂量 Pritelivir 后的质量平衡和代谢特征
Clinical Pharmacology in Drug Development ( IF 1.5 ) Pub Date : 2024-01-08 , DOI: 10.1002/cpdd.1358
Susanne Bonsmann ₁ , David McCormick ₂ , Jörg Pausch ₃ , Michiel de Vries ₄ , Melanie Sumner ₁ , Alexander Birkmann ₁ , Holger Zimmermann ₁ , Dirk Kropeit ₁

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Pritelivir 是一种具有抗 HSV 活性的解旋酶引物酶抑制剂。进行了两项人体质量平衡试验（一项多剂量试验和一项单剂量试验），以表征 100 mg 口服普替利韦联合单微剂量¹⁴ C-普利特利韦的吸收、分布、代谢和排泄。服药后 26 天收集血液、尿液和粪便样本。普替利韦的血浆半衰期为 63-67 小时。总体而言，多剂量试验和单剂量试验中分别回收了 92% 和 66% 的给药剂量。单剂量后的低恢复率 (66%) 最有可能与所使用的配方有关。主要代谢途径是酰胺水解，生成氨基噻唑磺酰胺（ATS）和吡啶基苯乙酸（PPA）。在血浆中，普替利韦、ATS、PPA和PPA-酰基葡萄糖苷酸占总放射性的40.6%、9.4%、5.1%和0.2%。超过 90% 的药物相关物质在服药后 624 小时内被消除。大部分通过尿液排出（75%和77%），其次是粪便（16%和23%）。尿液中的主要成分为PPA-酰基葡萄糖醛酸（及其异构体）、ATS及其N-去甲基化异构体。在粪便中仅观察到少量代谢物。总之，普替利韦的主要代谢途径已确定，主要排泄途径是肾脏。

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Mass Balance and Metabolite Profile after Single and Multiple Oral Doses of Pritelivir in Healthy Subjects

Pritelivir is a helicase-primase inhibitor active against HSV. Two human mass balance trials (a multiple-dose trial and a single-dose trial) were performed to characterize the absorption, distribution, metabolism, and excretion of 100 mg oral pritelivir combined with a single microdose of ¹⁴C-pritelivir. Blood, urine, and feces samples were collected up to 26 days postdose. The plasma half-life of pritelivir was 63-67 hours. Overall, 92% and 66% of the administered dose was recovered in the multiple and single dose trials, respectively. The low recovery after the single dose (66%) was most likely related to the formulation used. The major metabolic pathway was amide hydrolysis leading to amino thiazole sulfonamide (ATS) and pyridinyl phenyl acetic acid (PPA). In plasma, pritelivir, ATS, PPA, and PPA-acyl glucuronide accounted for 40.6%, 9.4%, 5.1%, and 0.2% of total radioactivity. More than 90% of drug-related material was eliminated 624 hours postdose. The majority was excreted in urine (75% and 77%), followed by feces (16% and 23%). The main components in urine were PPA-acyl glucuronide (and its isomers), ATS, and its N-demethylated isomers. Only minor metabolites were observed in feces. In conclusion, the major metabolic pathways of pritelivir have been identified with the primary excretion route being renal.

更新日期：2024-01-08

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