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

Abstract

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. 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. 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. Compared with a single dose of SHR2554 50 mg, the exposure of SHR2554 in vivo was significantly affected by the combined administration of itraconazole.