| Autor: |
Kunhong Deng, Yi Zou, Chan Zou, Hong Wang, Yuxia Xiang, Xiaoyan Yang, Shuang Yang, Chang Cui, Guoping Yang, Jie Huang |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Cancer Medicine, Vol 12, Iss 2, Pp 1431-1440 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2045-7634 |
| DOI: |
10.1002/cam4.5028 |
| Popis: |
Abstract Background SHR2554, a novel oral Enhancer of Zeste Homolog 2 inhibitor, shows broad‐spectrum anti‐tumor efficacy in preclinical studies. As SHR2554 is mainly metabolized by CYP3A4, it is helpful to conduct research on the effects of itraconazole, a strong inhibitor of CYP3A4‐metabolizing enzymes, on the pharmacokinetic characteristics and safety of SHR2554. Methods We conducted a single‐center, open‐label pharmacokinetic study of itraconazole on SHR2554 in 18 healthy Chinese subjects. Subjects were orally administrated SHR2554 50 mg on Day 1, itraconazole 200 mg Quaque Die (QD) from Days 4 to 7, SHR2554 50 mg co‐administrated with itraconazole 200 mg on Day 8, and itraconazole 200 mg QD from Days 9 to 12. Then, 4 ml of venous blood was collected at predetermined time points. Plasma SHR2554 concentrations were analyzed using a validated high‐performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using Phoenix WinNonlin v8.1. Results The Cmax of SHR2554 alone and in combination was 10.197 ± 7.0262 ng·ml−1 versus 70.538 ± 25.0219 ng·ml−1, AUC0–∞ was 50.99 ± 19.358 h·ng·ml−1 versus 641.53 ± 319.538 h·ng·ml−1, and AUC0–t was 28.70 ± 18.913 h·ng·ml−1 versus 612.13 ± 315.720 h·ng·ml−1. Co‐administration of SHR2554 and itraconazole caused 7.73‐, 12.47‐, and 23.75‐fold adjusted geometric mean ratios increases in SHR2554 Cmax, AUC0−∞ and AUC0−t respectively. The co‐administration regimen was well tolerated and had a good safety profile. Conclusions Compared with a single dose of SHR2554 50 mg, the exposure of SHR2554 in vivo was significantly affected by the combined administration of itraconazole. |
| Databáze: |
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