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.