TPN171与利福平或伊曲康唑共给药时药代动力学药物相互作用。

IF 3.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics Pub Date : 2025-09-01 DOI:10.1016/j.clinthera.2025.06.005

Liyu Liang MSc , Haiping Qin M.Med , Gangyi Liu BSc , Hongjie Qian PhD , Liang Xin MSc , Qingqing Wu M.Med , Chen Yu BSc , Zhen Wang PhD , Yu Wang PhD , Huaqing Duan MSc , Jingying Jia MSc

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引用次数: 0

摘要

目的：TPN171是一种新型的、高选择性的、有效的磷酸二酯酶5型（PDE5）抑制剂，目前正处于临床开发阶段，用于治疗肺动脉高压（PAH）和勃起功能障碍（ED）。该药物主要由细胞色素P450 （CYP）酶3A4代谢。我们评估了TPN171在中国健康志愿者中的药代动力学（PK）特征和安全性，无论是单独使用还是与伊曲康唑（一种CYP3A4有效抑制剂）或利福平（一种CYP3A4有效诱诱剂）联合使用。方法：在这项开放标签、固定序列的研究中，队列1在第1天和第6天口服TPN171 (10 mg)，每天1次，随后在第3天至第6天口服伊曲康唑（200 mg），每天1次。队列2在第1天和第10天口服TPN171 (20 mg)，每日1次，同时在第3天至第10天口服利福平（600 mg），每日1次。24名健康受试者入组（每组12人）。TPN171的PK参数通过非区室分析和血浆浓度检测来估计。比较与不同时给药伊曲康唑或利福平时TPN171的最大血浆浓度（Cmax）和外推至无穷大的浓度-时间曲线下面积（AUC0-∞）。结果：与单用TPN171相比，伊曲康唑联合治疗TPN171的Cmax和AUC0-∞分别提高了76.00%（最小二乘几何平均比（LSGMR）， 176.00% [90% CI, 160.37% ~ 193.15%]）和185.67% （LSGMR, 285.67% [90% CI, 261.87% ~ 311.64%]）。与单独使用TPN171相比，联合使用TPN171的Cmax和AUC0-∞分别降低74.53% （LSGMR, 25.47% [90% CI, 21.98% ~ 29.50%]）和90.14% （LSGMR, 9.86% [90% CI, 9.08% ~ 10.71%]）。阴茎自发勃起是最常见的不良反应，在24名受试者中发生了17例（70.83%）。结论：CYP3A4强效抑制剂和诱导剂可显著影响TPN171的暴露水平，尤其是诱导剂。因此，在服用TPN171时，建议避免与CYP3A4强效抑制剂或强效/中度诱导剂合用，或调整TPN171的剂量。

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Pharmacokinetic Drug Interactions of TPN171 When Coadministration With Rifampicin or Itraconazole

Purpose

TPN171, a novel, highly selective, and potent phosphodiesterase type 5 (PDE5) inhibitor, is currently under clinical development for the treatment of pulmonary arterial hypertension (PAH) and erectile dysfunction (ED). The drug is mainly metabolized by the cytochrome P450 (CYP) enzyme 3A4. We evaluated the pharmacokinetic (PK) profile and safety of TPN171, both alone and in combination with itraconazole (a CYP3A4 potent inhibitor) or rifampin (a CYP3A4 potent inducer), in healthy Chinese volunteers.

Methods

In this open-label, fixed-sequence study, TPN171 (10 mg) was administered orally once daily on Days 1 and 6 in Cohort 1, followed by oral itraconazole (200 mg) once daily from Days 3 to 6. Cohort 2 received oral TPN171 (20 mg) once daily on Days 1 and 10, with concurrent oral rifampin (600 mg) once daily administered from Days 3 to 10. Twenty-four healthy subjects were enrolled (12 per cohort). The PK parameters of TPN171 were estimated through noncompartmental analysis with its plasma concentration detection. Comparisons of the maximum plasma concentration (C_max) and the area under the concentration–time curve extrapolated to infinity (AUC_0-∞) for TPN171 were conducted between conditions with and without coadministration of itraconazole or rifampin.

Findings

The C_max and AUC_0-∞ for TPN171 were increased by 76.00% (least squares geometric mean ratios (LSGMR), 176.00% [90% CI, 160.37%–193.15%]) and 185.67% (LSGMR, 285.67% [90% CI, 261.87%–311.64%]) when combined with itraconazole versus TPN171 alone. The C_max and AUC_0-∞ of TPN171 were reduced by 74.53% (LSGMR, 25.47% [90% CI, 21.98%–29.50%]) and 90.14% when combined with rifampin versus TPN171 alone (LSGMR, 9.86% [90% CI, 9.08%–10.71%]). Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects.

Implications

CYP3A4 potent inhibitors and inducers can significantly affect the exposure level of TPN171, especially the inducers. Therefore, when taking TPN171, it is recommended to avoid concomitant administration with CYP3A4 potent inhibitors or potent/moderate inducers, or adjust the dosage of TPN171.

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来源期刊

Clinical therapeutics 医学-药学

CiteScore

6.00

自引率

3.10%

发文量

154

审稿时长

9 weeks

期刊介绍： Clinical Therapeutics provides peer-reviewed, rapid publication of recent developments in drug and other therapies as well as in diagnostics, pharmacoeconomics, health policy, treatment outcomes, and innovations in drug and biologics research. In addition Clinical Therapeutics features updates on specific topics collated by expert Topic Editors. Clinical Therapeutics is read by a large international audience of scientists and clinicians in a variety of research, academic, and clinical practice settings. Articles are indexed by all major biomedical abstracting databases.