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Study on pharmacokinetic interactions between SHR2554 and itraconazole in healthy subjects: A single-center,

Kunhong Deng¹, Yi Zou², Chan Zou¹

¹Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.

Cancer Medicine

|July 16, 2022

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.

Insights

Co-administering itraconazole significantly increases exposure to SHR2554, an Enhancer of Zeste Homolog 2 inhibitor, by over 7-fold. This combination was well-tolerated in healthy subjects, suggesting potential drug interactions to monitor in cancer patients.

Area of Science:

Pharmacology
Oncology
Drug Metabolism

Background:

SHR2554 is a novel oral Enhancer of Zeste Homolog 2 (EZH2) inhibitor with demonstrated anti-tumor activity.
SHR2554 is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme.
Itraconazole is a potent inhibitor of CYP3A4, necessitating investigation into its interaction with SHR2554.

Purpose of the Study:

To evaluate the pharmacokinetic (PK) interaction between SHR2554 and itraconazole.
To assess the safety and tolerability of co-administering SHR2554 with itraconazole.

Main Methods:

An open-label, single-center pharmacokinetic study was conducted in 18 healthy Chinese subjects.
Subjects received SHR2554 alone and in combination with itraconazole.
Plasma concentrations of SHR2554 were analyzed using LC-MS/MS, and PK parameters were calculated.

Main Results:

Co-administration with itraconazole resulted in substantial increases in SHR2554 exposure: 7.73-fold for Cmax, 12.47-fold for AUC0-∞, and 23.75-fold for AUC0-t.
The maximum concentration (Cmax) increased from 10.197 ng/mL to 70.538 ng/mL.
The area under the curve (AUC) showed significant increases, indicating higher overall drug exposure.

Conclusions:

Concomitant administration of itraconazole significantly impacts the in vivo pharmacokinetics of SHR2554.
The combination regimen was well-tolerated, indicating a favorable safety profile.
These findings highlight the need to consider potential drug-drug interactions when prescribing SHR2554 with CYP3A4 inhibitors.

Read full analysis

Keywords:

EZH2 inhibitor SHR2554 drug-drug interaction itraconazole pharmacokinetics

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