Abstract
Aims : A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inducer (rifampicin) on the pharmacokinetic profile of SHR2554, a novel enhancer of zeste homolog 2 inhibitor (EZH2) and CYP3A4 substrate.
Methods : Eighteen adult Chinese healthy subjects were enrolled in this study. All participants received a single oral dose of SHR2554 (300 mg) on day 1, rifampin (600 mg) from day 4 to day 10 and day 12, the same dose was coadministered with SHR2554 (300 mg) and rifampicin (600 mg) on day 11. The primary endpoints were SHR2554 exposure parameters. Lack of drug–drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration–time curve (AUC) or maximum concentration (Cmax), with/without oral rifampicin, were within a pre-specified interval (0.80–1.25).
Results : The Cmax, AUC0-t, and AUC0-∞ of administration alone and coadministration with rifampin were 177.265 ±127.9889 ng/mL, 17.001 ± 8.4759 ng/mL; 672.12 ± 507.390 h*ng/mL, 38.58 ± 19.495 h*ng/mL; and 721.50 ±514.386 h*ng/mL, 46.30 ± 20.750 h*ng/mL, respectively. Coadministration with rifampin decreased the least-squares geometric mean ratios of Cmax, AUC0-t, and AUC0-∞by 89%, 93%, and 93%, respectively. Well tolerance and acceptable safety profile showed during the trial.
Conclusion : The exposure of SHR2554 was significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of SHR2554 and strong inducers of CYP3A4.
Keywords: SHR2554, cytochrome P450, drug-drug interaction, pharmacokinetics, drug metabolism, drug safety
1 Introduction
Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which regulates its downstream gene expression through tri-methylation of lysine 27 of histone H3 (H3K27)[1]. According to previous research, EZH2 regulates cell progression in three ways including PRC2-dependent H3K27 methylation, PRC2-dependent non-histone protein methylation, and PRC2-independent gene transactivation.[2-4]. EZH2 hyperactivity, overexpression, or expression loss is correlated with cancer initiation[5], progression[6], and immunity regulation[7] due to enhanced cell proliferation and oncogenic capacity. Several cancers are associated with the EZH2 overexpression, such as hepatocellular carcinoma[8], gastric cancer[9], relapsed/refractory follicular lymphoma[10], advanced epithelioid sarcoma[11], etc. A host of studies have demonstrated that specific EZH2 inhibitors or gene knockout could reduce EZH2-related tumors development and progression[12]. Based on these founds, several specific EZH2 inhibitors that ongoing clinical trials of drugs have been developed for treatment, including GSK126, EPZ005687, EI1, tazemetostat, EPZ011989, UNC1999, etc[13].
SHR2554, a novel highly selective oral EZH2 inhibitor which inhibits both wild-type and mutant EZH2 methyltransferase activity, is developed by Jiangsu Hengrui Medicine co., Ltd. Preclinical studies have shown that SHR2554 competitively binds to the catalytic SET domain of EZH2 to inhibit mouse lymphoma cell proliferation and tumor growth[14]. SHR2554 expressed excellent application prospects for EZH2 wild-type Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) patients with an objective response rate lower by 20% after treatment using EZH2-specific inhibitors[14]. And phase I clinical study indicated aiming to relapsed or refractory lymphoma patients, SHR2554 showed an acceptable safety profile and promising anti-tumor activity[15]. Further clinical trials for SHR2554 administration alone or coadministration with other anti-tumor drugs aimed at malignant tumor, prostate cancer, castration-resistant prostate cancer, solid tumor, and lymphoma are ongoing (NCT05661591, NCT05592262, NCT04407741, NCT05049083). Hence, SHR2554 provides a new therapeutic modality for patients with multiple abnormal EZH2 expression tumors.
The results in the phase I study have demonstrated that 350 mg SHR2554 twice daily is the maximum tolerated dose[15], so the dosage of below 300mg (including 300mg) has good safety without occurring drug-related SAE or dose-limiting toxicity. CYP3A4 enzyme involves in the SHR2554 main oxidative metabolism, considering many drugs could inhibit or induce CYP3A4 expression, coadministration with such medicines could significantly affect it pharmacokinetics of SHR2554, so it is essential to conduct drug-drug interaction (DDI) clinical trials for CYP3A4 inhibitors or CYP3A4 inducers. In addition, strong index inhibitors or strong index inducers should be urgently prioritized in clinical DDI trials when the investigational drug is substrate based on the guidelines. Therefore, this study is designed to evaluate the concomitant use of rifampin, a potentially potent CYP3A4 inducer, to impact the pharmacokinetics (PK) properties of SHR2554 in healthy Chinese volunteers. Safety and tolerance are assessed during treatment period.