Translational Clinical Sciences, Research and Development, Pfizer, Bothell, Washington, USA.
Clinical Pharmacology and Translational Sciences, Oncology Research and Development, Pfizer, Bothell, Washington, USA.
Br J Clin Pharmacol. 2024 Sep;90(9):2299-2313. doi: 10.1111/bcp.16128. Epub 2024 Jun 12.
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.
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.
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.
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.
我们研究了在血液恶性肿瘤中博纳吐单抗维迪西妥（BV）抗体药物偶联物（ADC）和单甲基奥瑞他汀 E 的药代动力学和暴露-反应关系。
这项群体药代动力学分析包括来自五项成人和三项儿科研究的数据。根据 BV 1.8mg/kg（最大 180mg）每 3 周静脉注射的方案，模拟了虚拟成人和儿科人群中的暴露情况。临床终点包括总缓解率、≥2 级周围神经病变（PN）和≥3 级中性粒细胞减少症。
BV ADC 表现出线性药代动力学，可通过三房室模型很好地描述，体重是唯一对暴露有显著影响的协变量。单甲基奥瑞他汀 E 表现出随时间变化的形成率。12 至<18 岁患者的稳态 BV ADC 暴露与成人患者相似，但 2 至<12 岁患者的暴露水平低 23%-38%。尽管暴露水平较低，但在 2 至<12 岁的患者中，每 3 周给予 BV 1.8mg/kg 仍观察到临床活性（总缓解率：2 至<12 岁，60%；12 至<18 岁，43%）。在成人中，但不是儿科患者中，BV ADC 暴露增加与≥2 级 PN 和≥3 级中性粒细胞减少症的发生相关。
成人和儿科患者的 BV 药代动力学一致。2 至<12 岁患者的 BV ADC 暴露水平低于≥12 岁患者，但在疗效、≥2 级 PN 或≥3 级中性粒细胞减少症方面没有观察到明显的临床相关差异。这些数据支持根据体重为患者给药，无论年龄大小；因此，2 至<12 岁患者无需调整剂量。
