Journal de pathologie clinique et expérimentale

Abstrait

Quantifying Induction/Inhibition Effects on Fuzuloparib Using a Physiologically Based Pharmaco-Kinetic (PBPK) model

Jingxi Li, Keheng Wu, Xue Li, Sihui Long, Zhou Zhou, Youni Zhao, Ranran Jia, Pingping Song, Jack Liu, Bo Liu

Fuzuloparib was approved in China in 2020 for treating ovarian and other solid cancers in patients with germline BRCA (breast cancer gene) receiving second-line or above chemotherapy. It is a Poly Adenosine diphosphate-Ribose Polymerase (PARP) inhibitor developed by Jiangsu Hengrui Medicine Co., Ltd. PARP inhibits DNA repair in cancer cells, induces cell cycle arrest and further inhibits tumour cell proliferation. The main metabolic enzyme involved in fuzuloparib is CYP3A4/5. The purpose of this study is to use the PBPK model to predict and compare the effects of the inducers and inhibitors on the Pharmaco-Kinetics (PK) of fuzuloparib. Based on the in vivo and in vitro data, a PKPB model was developed using B₂O simulator (Shanghai Yinghan Pharmaceutical Technology Co., Ltd). The model was verified using the clinical study of fuzuloparib with moderate inhibitor fluconazole and strong inducer rifampicin. After validation, the model was used to predict the effects of the mild inhibitor fluvoxamine and moderate inducer efavirenz on fuzuloparib exposure in vivo. No clinical study has been published to investigate the effects of efavirenz or fluvoxamine on fuzuloparib. The model predicted that the AUC0-t of fuzuloparib under the action of the efavirenz and fluvoxamine were 0.71 and 1.14 times of the original, respectively. It is suggested that efavirenz significantly affects fuzuloparib exposure and should be avoided when used together with fuzuloparib. Fluvoxamine 50 mg has no significant effect on fuzuloparib exposure. Higher doses of fluvoxamine increase the risk and should be used with caution.