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 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.