Journal Article

Pharmacokinetic Drug Interactions of TPN171 When Coadministration With Rifampicin or Itraconazole

Wu, Qingqing, Xin, Liang, Duan, Huaqing, Qin, Haiping, Wang, Yu, Liu, Gangyi, Qian, Hongjie, Yu, Chen, Wang, Zhen, Jia, Jingying, Liang, Liyu

2025

Overview

•TPN171 is a self-developed PDE5 inhibitor used to treat Pulmonary arterial hypertension and erectile dysfunction with the advantages of high activity, good selectivity, low toxicity, rapid oral absorption, and long half-life in vivo.•The Cmax and AUC0-∞ for TPN171 were increased by 76.00% and 185.67% when combined with itraconazole versus TPN171 alone, and reduced by 74.53% and 90.14% when combined with rifampin versus TPN171 alone.•Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects.•TPN171 demonstrated a favorable safety profile and was well-tolerated in healthy subjects, whether administered as monotherapy or co-administered with the CYP3A4 inhibitor itraconazole or inducer rifampicin.•TPN171 exhibits a significant interaction with CYP3A4 inhibitors/inducers. 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. 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-∞) for TPN171 were conducted between conditions with and without coadministration of itraconazole or rifampin. The Cmax and AUC0-∞ 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-∞ 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. 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.

• Publisher: Elsevier Inc,Elsevier Limited
• Subject: Administration, Oral / Adult / Area Under Curve / Clinical outcomes / Clinical trials / Cytochrome / Cytochrome P-450 CYP3A - metabolism / Cytochrome P-450 CYP3A Inducers - administration & dosage / Cytochrome P-450 CYP3A Inducers - adverse effects / Cytochrome P-450 CYP3A Inducers - pharmacokinetics / Cytochrome P-450 CYP3A Inducers - pharmacology / Cytochrome P-450 CYP3A Inhibitors - administration & dosage / Cytochrome P450 / Cytochrome P450 3A4 / Drug dosages / Drug interaction / Drug Interactions / Enzymes / Erectile dysfunction / FDA approval / Healthy Volunteers / Hepatitis / Humans / Internal Medicine / Itraconazole / Itraconazole - administration & dosage / Itraconazole - adverse effects / Itraconazole - pharmacokinetics / Itraconazole - pharmacology / Kinases / Male / Metabolism / Metabolites / Middle Aged / Nonprescription drugs / Oral administration / Penis / Pharmaceuticals / Pharmacokinetics / Phosphodiesterase 5 Inhibitors - administration & dosage / Phosphodiesterase 5 Inhibitors - adverse effects / Phosphodiesterase 5 Inhibitors - pharmacokinetics / Plasma / Rifampin / Rifampin - administration & dosage / Rifampin - adverse effects / Rifampin - pharmacokinetics / Rifampin - pharmacology / Safety / TPN171 / Young Adult