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, on...

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Published in:Cancer medicine (Malden, MA) Vol. 12; no. 2; pp. 1431 - 1440
Main Authors: Deng, Kunhong, Zou, Yi, Zou, Chan, Wang, Hong, Xiang, Yuxia, Yang, Xiaoyan, Yang, Shuang, Cui, Chang, Yang, Guoping, Huang, Jie
Format: Journal Article
Language:English
Published: United States John Wiley & Sons, Inc 01.01.2023
John Wiley and Sons Inc
Wiley
Subjects:
Antifungal agents
Area Under Curve
Body mass index
Cancer
Cell cycle
Cell growth
Confidence intervals
Cross-Over Studies
Cytochrome P-450 CYP3A
Drug dosages
drug–drug interaction
Enzyme Inhibitors
EZH2 inhibitor
Healthy Volunteers
Hepatitis
High-performance liquid chromatography
Humans
Itraconazole
Itraconazole - pharmacology
Laboratories
Lymphoma
Mass spectroscopy
Neoplasms
Oral administration
Pharmaceuticals
Pharmacokinetics
Plasma
SHR2554
Tumors
Vital signs
pharmacokinetics
SHR2554
itraconazole
EZH2 inhibitor
drug-drug interaction
ISSN:2045-7634, 2045-7634
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Summary: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. Compared with a single dose of SHR2554 50 mg, the exposure of SHR2554 in vivo was significantly elevated by the combined administration of itraconazole. The co‐administration regimen was well tolerated and had a good safety profile.
Bibliography:Kunhong Deng and Yi Zou share first authorship.
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ISSN:2045-7634
2045-7634
DOI:10.1002/cam4.5028