Effect of a strong CYP3A4 inducer rifampin on the pharmacokinetics of
SHR2554 in healthy Chinese volunteers: A drug-drug interaction study
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.