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Study on pharmacokinetic interactions between SHR2554 and itraconazole in healthy subjects: A single‐center, open‐label phase I trial

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, o...

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Detalles Bibliográficos
Autores principales: Deng, Kunhong, Zou, Yi, Zou, Chan, Wang, Hong, Xiang, Yuxia, Yang, Xiaoyan, Yang, Shuang, Cui, Chang, Yang, Guoping, Huang, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9883540/
https://www.ncbi.nlm.nih.gov/pubmed/35841331
http://dx.doi.org/10.1002/cam4.5028
Descripción
Sumario: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 C (max) of SHR2554 alone and in combination was 10.197 ± 7.0262 ng·ml(−1) versus 70.538 ± 25.0219 ng·ml(−1), AUC(0–∞) was 50.99 ± 19.358 h·ng·ml(−1) versus 641.53 ± 319.538 h·ng·ml(−1), and AUC(0–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 C (max), AUC(0−∞) and AUC(0−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.