Abstract：
OBJECTIVE: We studied the pharmacokinetics and exposure-response relationships of the brentuximab vedotin (BV) antibody-drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies.
METHODS: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia.
RESULTS: BV ADC exhibited linear pharmacokinetics, well-described by a three-compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time-varying formation rate. Simulated steady-state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%-38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence.
CONCLUSIONS: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight-based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted.
METHODS: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia.
RESULTS: BV ADC exhibited linear pharmacokinetics, well-described by a three-compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time-varying formation rate. Simulated steady-state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%-38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence.
CONCLUSIONS: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight-based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted.
摘要：
目的：我们研究了本妥昔单抗维多汀（BV）抗体-药物偶联物（ADC）和未偶联的单甲基奥瑞他汀E在血液恶性肿瘤中的药代动力学和暴露-反应关系。
方法：该群体药代动力学分析包括来自5项成人和3项儿科研究的数据。模拟了每3周静脉注射BV1.8mg/kg（最大180mg）后虚拟成人和儿科人群的暴露情况。临床终点包括总反应率，≥2级周围神经病变（PN）和≥3级中性粒细胞减少症。
结果：BVADC表现出线性药代动力学，用三室模型很好地描述，体重是暴露的唯一重要协变量。单甲基奥瑞他汀E的形成速率随时间变化。12至<18岁患者的模拟稳态BVADC暴露与成年患者相似，但在2至<12岁的患者中降低了23%-38%。尽管曝光率较低，在2至<12岁的人群中，每3周观察到BV1.8mg/kg的临床活动（总反应率：2至<12岁，60%；12至<18岁，43%）。在成人，但不是儿科患者，BVADC暴露增加与≥2级PN和≥3级中性粒细胞减少症的发生相关.
结论：成人和儿科患者的BV药代动力学是一致的。2至<12岁患者的BVADC暴露较低，而不是≥12年，但疗效没有明显的临床相关差异，观察到≥2级PN或≥3级中性粒细胞减少.这些数据支持患者基于体重的BV剂量，无论年龄如何；因此，在2至<12年的剂量调整似乎没有必要。
方法：该群体药代动力学分析包括来自5项成人和3项儿科研究的数据。模拟了每3周静脉注射BV1.8mg/kg（最大180mg）后虚拟成人和儿科人群的暴露情况。临床终点包括总反应率，≥2级周围神经病变（PN）和≥3级中性粒细胞减少症。
结果：BVADC表现出线性药代动力学，用三室模型很好地描述，体重是暴露的唯一重要协变量。单甲基奥瑞他汀E的形成速率随时间变化。12至<18岁患者的模拟稳态BVADC暴露与成年患者相似，但在2至<12岁的患者中降低了23%-38%。尽管曝光率较低，在2至<12岁的人群中，每3周观察到BV1.8mg/kg的临床活动（总反应率：2至<12岁，60%；12至<18岁，43%）。在成人，但不是儿科患者，BVADC暴露增加与≥2级PN和≥3级中性粒细胞减少症的发生相关.
结论：成人和儿科患者的BV药代动力学是一致的。2至<12岁患者的BVADC暴露较低，而不是≥12年，但疗效没有明显的临床相关差异，观察到≥2级PN或≥3级中性粒细胞减少.这些数据支持患者基于体重的BV剂量，无论年龄如何；因此，在2至<12年的剂量调整似乎没有必要。
