Turner David C, Navid Fariba, Daw Najat C, Mao Shenghua, Wu Jianrong, Santana Victor M, Neel Michael, Rao Bhaskar, Willert Jennifer Reikes, Loeb David M, Harstead K Elaine, Throm Stacy L, Freeman Burgess B, Stewart Clinton F
Authors' Affiliations: Departments of Pharmaceutical Sciences, Oncology, Biostatistics, and Surgery; Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas; Department of Pediatrics, Stanford School of Medicine, Palo Alto, California; and Department of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
Authors' Affiliations: Departments of Pharmaceutical Sciences, Oncology, Biostatistics, and Surgery; Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas; Department of Pediatrics, Stanford School of Medicine, Palo Alto, California; and Department of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MarylandAuthors' Affiliations: Departments of Pharmaceutical Sciences, Oncology, Biostatistics, and Surgery; Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas; Department of Pediatrics, Stanford School of Medicine, Palo Alto, California; and Department of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
Clin Cancer Res. 2014 May 15;20(10):2783-92. doi: 10.1158/1078-0432.CCR-13-2364. Epub 2014 Mar 17.
To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes.
Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression.
Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P < 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P < 0.05).
A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications.
描述儿科患者中贝伐单抗处置的个体间变异性来源，并探讨贝伐单抗药代动力学与临床伤口愈合结果之间的关联。
在肿瘤切除术前，对参加多机构骨肉瘤试验的患者（中位年龄12.2岁）给予三剂贝伐单抗（15mg/kg）。从27名患者中获取用于贝伐单抗药代动力学的系列样本。将群体药代动力学模型与数据拟合，并系统地测试患者人口统计学和临床化学值作为模型参数的预测协变量。通过逻辑回归评估贝伐单抗暴露与伤口愈合状态之间的关联。
两室模型充分描述了贝伐单抗浓度-时间数据。药代动力学参数估计值与先前在成人中报道的相似，中位（范围）终末半衰期较长，为12.2天（8.6至32.4天），分布容积表明主要局限于血管空间，为49.1mL/kg（27.1至68.3mL/kg）。身体组成是贝伐单抗暴露的关键决定因素，因为体重指数百分位数与体重标准化清除率和分布容积显著（P<0.05）相关。此外，原发性肿瘤切除术前的贝伐单抗暴露与术后重大伤口愈合并发症风险增加相关（P<0.05）。
建立了贝伐单抗的群体药代动力学模型，该模型表明基于体重给药时贝伐单抗暴露的变异性与身体组成有关。使用理想体重进行贝伐单抗剂量换算将通过最小化药代动力学变异性并降低重大伤口愈合并发症的可能性，为儿童提供一种改进的给药方法。
