A multicenter randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Caelyx ® in advanced breast cancer

Yinjuan Li; Lu Qi; Yu Wang; Yan Li; Chunpu Lei; Yingjuan Zhang; Xiaoqiang Cheng; Ju Liu; HaiHong Bai; Xia Zhao; Shuzhen Lv; Bingjun Xiong; Juan Liu; Yehui Shi; Huan Zhou; Hongtao Li; Lihong Liu; Hongchuan Jiang; Weiwei Ouyang; Xiaowen Li; Yanping Li; Xinghe Wang

doi:10.3389/fonc.2022.1070001

A multicenter randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Caelyx ^® in advanced breast cancer

Front Oncol. 2022 Dec 20:12:1070001. doi: 10.3389/fonc.2022.1070001. eCollection 2022.

Authors

Yinjuan Li¹, Lu Qi¹, Yu Wang¹, Yan Li¹, Chunpu Lei¹, Yingjuan Zhang¹, Xiaoqiang Cheng¹, Ju Liu¹, HaiHong Bai¹, Xia Zhao², Shuzhen Lv², Bingjun Xiong², Juan Liu², Yehui Shi³, Huan Zhou⁴, Hongtao Li⁵, Lihong Liu⁶, Hongchuan Jiang⁷, Weiwei Ouyang⁸, Xiaowen Li⁹, Yanping Li², Xinghe Wang¹

Affiliations

¹ Department of Phase I Clinical Trial Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
² Department of Breast Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
³ Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
⁴ National Institute of Drug Clinical Trial, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
⁵ Oncology Department, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China.
⁶ Pharmacy Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
⁷ Department of Breast Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
⁸ Oncology Department, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, China.
⁹ Clinical Medical Center General Manager Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China.

Abstract

Purpose: To compare the pharmacokinetic (PK) bioequivalence (BE) and safety of a generic pegylated liposomal doxorubicin (PLD) formulation with the reference product Caelyx^®.

Methods: A multicenter, single-dose, open-label, randomized, two-way crossover study was conducted in patients with breast cancer. For each period, the patients were administered with the test or the reference PLD intravenously at a dose of 50 mg/m². C_max, AUC_0-t and AUC_0-∞ for free, and encapsulated doxorubicin (doxorubicin) and partial AUC (AUC_0-48h, AUC_48h-t) for encapsulated doxorubicin were evaluated in 17 blood samples taken predose, and increasing time intervals over the following 14 days in each period. A washout period of 28-35 days was observed before crossing over.

Results: 48 patients were enrolled and randomised, of which 44 were included and analysed in bioequivalence set (BES). The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of C_max, AUC_0-t and AUC_0-∞ for free doxorubicin and encapsulated doxorubicin all fall within the bioequivalent range of 80% to 125%. The 90% CIs of GMR of partial AUC (AUC_0-48h, AUC48_h-t) for encapsulated doxorubicin also fall within the bioequivalent range. 48 patients were all included in the safety set (SS). The incidence of treatment-emergent adverse events (TEAEs) related to T and R was 95.8% (46/48) and 97.8% (45/46) respectively. The highest incidence of TEAEs was various laboratory abnormalities. 2 patients withdrew due to T-drug-related AEs. Only one patient experienced serious adverse events and no death occurred in this study. There were no significant differences between the safety profiles of the generic formulation and Caelyx^®.

Conclusions: Bioequivalence between the test and the reference products was established for free and encapsulated doxorubicin.

Clinical trial registration: http://www.chinadrugtrials.org.cn, identifier [CTR20210375].

Keywords: bioequivalence; breast cancer; encapsulated doxorubicin; free doxorubicin; pegylated liposomal doxorubicin (PLD); pharmacokinetics.