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Drug-drug interaction potential of SH-1028, a third-generation EGFR-TKI: in vitro and clinical trials

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Abstract

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)

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the “512 Talent Fund” of Bengbu Medical College (BY51201313, China) and the Research and development project commissioned by Nanjing Sanhome Pharmaceutical Co., Ltd(2021043).

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Author notes

  1. Xiaoli Li and Yuyan Liu have made equal contributions to this work.

Authors and Affiliations

  1. Clinical Trial Center, The First Affiliated Hospital of Bengbu Medical College, 233009, Bengbu, China

    Xiaoli Li, Minhui Zhu, Cuixia He, Yuanyuan Xu, Jiaxiang Ding, Ying Wang, Rongfang Shan, Bingyan Liu, Yuzhou Ding, Jing Xie, Huan Zhou & Yuanyuan Liu

  2. School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China

    Yuyan Liu

  3. School of Pharmacy, Bengbu Medical College, 233030, Bengbu, China

    Minhui Zhu, Cuixia He, Yuanyuan Xu, Ying Wang, Rongfang Shan, Huan Zhou & Yuanyuan Liu

  4. School of Public Foundation, Bengbu Medical College, 233030, Bengbu, China

    Jiaxiang Ding & Huan Zhou

  5. Nanjing Sanhome Pharmaceutical Co., Ltd, 210000, Nanjing, China

    Zhiqiang Wang

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  1. Xiaoli Li
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Contributions

YY-L, ZQ-W and H-Z contributed to the conception and design. XL-L and YY-L provided medical supervision. MH-Z and CX-H drafted the manuscript, and YY-X conducted the analysis and interpretation of the data. JX-D designed figures and tables, and reviewed the grammar. Y-W contributed to the management of drug and biological sample disposition. RF-S contributed to quality control throughout the study. BY-L contributed to the study organization and implementation. YZ-D and J-X participated in the sample collection. All authors were involved in revising the paper critically for intellectual content and the final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Yuanyuan Liu.

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We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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This study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the institutional review boards of all participating sites.

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Written informed consent was obtained from all the participants included in the study.

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Li, X., Liu, Y., Zhu, M. et al. Drug-drug interaction potential of SH-1028, a third-generation EGFR-TKI: in vitro and clinical trials. Invest New Drugs 41, 453–462 (2023). https://doi.org/10.1007/s10637-023-01356-5

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  • DOI: https://doi.org/10.1007/s10637-023-01356-5

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