期刊
INVESTIGATIONAL NEW DRUGS
卷 41, 期 3, 页码 453-462出版社
SPRINGER
DOI: 10.1007/s10637-023-01356-5
关键词
SH-1028; Drug metabolism; Drug-drug interaction; Pharmacokinetics
SH-1028 is a third-generation EGFR tyrosine kinase inhibitor used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC). This study investigated the drug-drug interaction (DDI) potential of SH-1028 through in vitro experiments and clinical trials. In vitro studies showed that SH-1028 was primarily metabolized by CYP3A4 and had slight inhibitory effects on the activities of CYP1A2, 2B6, 2C19, 2D6, and 3A4 enzymes. The phase I clinical trial demonstrated that co-administration of rifampicin (a CYP3A4 inducer) and itraconazole (a CYP3A4 inhibitor) affected the pharmacokinetics of SH-1028. While SH-1028 did not significantly induce or inhibit human CYPs at the clinically expected dose, interactions with CYP3A4-affecting drugs or foods should be closely monitored during the clinical use of SH-1028. (Clinical trial registration number: CTR20210558)
SH-1028 is an irreversible third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Considering the possibility of combination therapy in patients with NSCLC, we investigated the drug-drug interaction (DDI) potential of SH-1028 both in vitro and in clinical trials. The in vitro studies were conducted to determine the potential of SH-1028 as a substrate, inducer, or inhibitor of cytochrome P450 (CYP) subtypes. A phase I drug-drug interaction study in healthy volunteers was performed to evaluate the impact of co-administering rifampicin (a strong CYP3A4 inducer) and itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of SH-1028. The in vitro experiments showed that SH-1028 was mainly metabolized by CYP3A4. The activities of CYP1A2, 2B6, 2C19, 2D6 and 3A4 enzymes were slightly inhibited in vitro with SH-1028. SH-1028 has no obvious induction effect on CYP1A2 and CYP2B6 activities, but has potential induction effect on CYP3A4 mRNA expression. However, SH-1028 may not induce or inhibit human CYPs significantly at the clinically expected dose (200 mg). The geometric mean ratios of pharmacokinetic parameters and their corresponding 90% confidence intervals for SH-1028 in combination and alone did not fall within the range of 80-125%. It is speculated that itraconazole and rifampicin affect the metabolism of SH-1028. In the clinical application of SH-1028, special attention should be paid to the interaction between SH-1028 and drugs or foods that affect the activity of CYP3A4. (Clinical trial registration number: CTR20210558)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据