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Pharmacokinetic Drug Interactions of TPN171 When Coadministration With Rifampicin or Itraconazole

文献类型：期刊论文

作者Liang, Liyu2,3; Qin, Haiping2; Liu, Gangyi2,3; Qian, Hongjie2,3; Xin, Liang2,3; Wu, Qingqing2,3; Yu, Chen2,3; Wang, Zhen1; Wang, Yu1; Duan, Huaqing4
刊名CLINICAL THERAPEUTICS
出版日期2025-09-01
卷号47期号:9页码:706-712
关键词Drug interactions Pharmacokinetics Safety TPN171
ISSN号0149-2918
DOI10.1016/j.clinthera.2025.06.005
英文摘要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 (Cmax ) and the area under the concentration-time curve extrapolated to infinity (AUC0- infinity) for TPN171 were conducted between conditions with and without coadministration of itraconazole or rifampin. Findings: The Cmax and AUC0- infinity 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 Cmax and AUC0- infinity 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.
WOS关键词ERECTILE DYSFUNCTION ; SEXUAL DYSFUNCTION ; PHOSPHODIESTERASE ; INHIBITORS
资助项目Vigonvita Life Sciences Co, Ltd (Suzhou, China) ; Science and Technology Committee of Shanghai Municipality[18DZ2250500] ; Science and Technology Committee of Shanghai Municipality[23DZ2291800]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001570447500009
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/321528]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Jia, Jingying
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
2.Fudan Univ, Shanghai Xuhui Cent Hosp, Zhongshan Xuhui Hosp, 366 Longchuan North Rd, Shanghai, Peoples R China
3.Shanghai Engn Res Ctr Phase I Clin Res & Qual Con, Shanghai, Peoples R China
4.Vigonvita Life Sci Co Ltd, Suzhou, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Liyu,Qin, Haiping,Liu, Gangyi,et al. Pharmacokinetic Drug Interactions of TPN171 When Coadministration With Rifampicin or Itraconazole[J]. CLINICAL THERAPEUTICS,2025,47(9):706-712.
APA Liang, Liyu.,Qin, Haiping.,Liu, Gangyi.,Qian, Hongjie.,Xin, Liang.,...&Jia, Jingying.(2025).Pharmacokinetic Drug Interactions of TPN171 When Coadministration With Rifampicin or Itraconazole.CLINICAL THERAPEUTICS,47(9),706-712.
MLA Liang, Liyu,et al."Pharmacokinetic Drug Interactions of TPN171 When Coadministration With Rifampicin or Itraconazole".CLINICAL THERAPEUTICS 47.9(2025):706-712.

入库方式： OAI收割

来源：上海药物研究所

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