Fangfang Ding1, Jie Huang2, Zeying Feng1, Yun Kuang2, Shuang Yang2, Yuxia Xiang2, Chan Zou3, Guoping Yang4,5. 1. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, China. 2. Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China. 3. Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China. zouchan107@gmail.com. 4. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, China. ygp9880@126.com. 5. Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China. ygp9880@126.com.
Abstract
PURPOSE: This study aimed to compare the safety, tolerability, pharmacokinetics (PK), and bioequivalence of a test humanized recombinant monoclonal antibody targeting human epidermal growth factor receptor-2 (HER-2) with the reference Herceptin®. MATERIALS AND METHODS: The trial consisted of two parts (part I and part II). Part I was an open-label, sequential-cohort dose-escalation study, where 16 healthy subjects were either intravenously infused with QLHER2 (test) at single doses escalating from 0.2 to 6 mg/kg (0.2, 1, 2, 4, and 6 mg/kg) or given 4 mg/kg Herceptin (reference) for evaluating the safety, tolerability, and PK of QLHER2. Part II was a randomized, double-blind, parallel-group study to evaluate the bioequivalence of QLHER2 and Herceptin in 60 subjects. RESULTS: Following a 1.5-h intravenous infusion of single ascending doses of QLHER2 (1, 2, 4, or 6 mg/kg) in part I, Cmax and Tmax were 19.43-120.01 μg/mL and 68.91-157.87 h, respectively. AUC0-t and CL were 1.91-34.21 h·μg/mL and 0.54-0.12 mL/h/kg, indicating lower clearance at higher doses, with a greater than proportional increase in AUC0-t and t1/2 of 68.91-157.87 h. In part II, serum concentrations were comparable between QLHER2 and Herceptin over a 70-day sampling period, and the QLHER2/Herceptin ratios of Cmax and AUC0-t were 105.90% [90% confidence interval (CI): 95.69%-117.26%] and 95.79% (90% CI: 87.74%-106.40%), respectively. CONCLUSION: The 90% CI value of Cmax and AUC0-t for QLHER2/Herceptin ratio ranged between 80.0%-125.00%, indicating that QLHER2 was bioequivalent to Herceptin. These results support further evaluation of QLHER2. Trial registration number: ChiCTR2000041577 and ChiCTR2100041802. Date of registration: 30th December, 2020 and 5th January 2021.
PURPOSE: This study aimed to compare the safety, tolerability, pharmacokinetics (PK), and bioequivalence of a test humanized recombinant monoclonal antibody targeting human epidermal growth factor receptor-2 (HER-2) with the reference Herceptin®. MATERIALS AND METHODS: The trial consisted of two parts (part I and part II). Part I was an open-label, sequential-cohort dose-escalation study, where 16 healthy subjects were either intravenously infused with QLHER2 (test) at single doses escalating from 0.2 to 6 mg/kg (0.2, 1, 2, 4, and 6 mg/kg) or given 4 mg/kg Herceptin (reference) for evaluating the safety, tolerability, and PK of QLHER2. Part II was a randomized, double-blind, parallel-group study to evaluate the bioequivalence of QLHER2 and Herceptin in 60 subjects. RESULTS: Following a 1.5-h intravenous infusion of single ascending doses of QLHER2 (1, 2, 4, or 6 mg/kg) in part I, Cmax and Tmax were 19.43-120.01 μg/mL and 68.91-157.87 h, respectively. AUC0-t and CL were 1.91-34.21 h·μg/mL and 0.54-0.12 mL/h/kg, indicating lower clearance at higher doses, with a greater than proportional increase in AUC0-t and t1/2 of 68.91-157.87 h. In part II, serum concentrations were comparable between QLHER2 and Herceptin over a 70-day sampling period, and the QLHER2/Herceptin ratios of Cmax and AUC0-t were 105.90% [90% confidence interval (CI): 95.69%-117.26%] and 95.79% (90% CI: 87.74%-106.40%), respectively. CONCLUSION: The 90% CI value of Cmax and AUC0-t for QLHER2/Herceptin ratio ranged between 80.0%-125.00%, indicating that QLHER2 was bioequivalent to Herceptin. These results support further evaluation of QLHER2. Trial registration number: ChiCTR2000041577 and ChiCTR2100041802. Date of registration: 30th December, 2020 and 5th January 2021.
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