Sohn Winnie, Simiens Mary Ann, Jaeger Kelly, Hutton Shauna, Jang Graham
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA.
Br J Clin Pharmacol. 2014 Sep;78(3):477-87. doi: 10.1111/bcp.12355.
The objective of this systematic review was to characterize the pharmacokinetics and pharmacodynamics of denosumab (XGEVA®), a fully human IgG2 monoclonal antibody which binds to receptor activator of nuclear factor kappa-B ligand (RANKL), for the treatment of skeletal-related events (SREs) in patients with advanced cancer and bone metastases.
A total of 708 patients (116 healthy patients and 592 patients with solid tumours or multiple myeloma and bone metastases) included in seven clinical studies were evaluated for denosumab pharmacokinetics. Denosumab was administered as a single subcutaneous (s.c.) dose or multiple s.c. doses, ranging from 0.1 to 3.0 mg kg(-1) or 30 mg to 180 mg fixed dosing, every 1 or 3 months for up to 45 months.
Consistent with the results in healthy adults, single s.c. doses of denosumab demonstrated dose-dependent, non-linear pharmacokinetics in advanced cancer patients with bone metastases across a wide dose range (0.1-3.0 mg kg(-1) ). Reductions in levels of the bone turnover marker, uNTx/Cr, were observed within 1 day. The duration of reductions generally increased with dose and dosing frequency. In patients with solid tumours and bone metastases, pharmacokinetics and pharmacodynamic comparisons across tumour types and concomitant cancer therapies (chemotherapies and/or hormone therapies) suggest that neither tumour type nor type of concomitant therapy markedly affects denosumab pharmacokinetics or pharmacodynamics.
Denosumab displayed non-linear pharmacokinetics at doses below 60 mg but at higher doses, denosumab exposure increased approximately dose-proportionally in advanced cancer patients with bone metastases. Following a 120 mg, every 4 weeks dosing schedule, similar denosumab pharmacokinetics and pharmacodynamics were observed across tumour types and were independent of concomitant cancer therapies.
本系统评价的目的是描述地诺单抗（XGEVA®）的药代动力学和药效学特征。地诺单抗是一种全人IgG2单克隆抗体，可与核因子κB受体活化因子配体（RANKL）结合，用于治疗晚期癌症和骨转移患者的骨相关事件（SREs）。
对7项临床研究中纳入的708例患者（116例健康患者以及592例患有实体瘤或多发性骨髓瘤并伴有骨转移的患者）进行地诺单抗药代动力学评估。地诺单抗采用单次皮下注射剂量或多次皮下注射剂量给药，剂量范围为0.1至3.0mg/kg或30mg至180mg固定剂量，每1或3个月给药一次，最长达45个月。
与健康成年人的结果一致，单次皮下注射地诺单抗在广泛的剂量范围（0.1 - 3.0mg/kg）内，在患有骨转移的晚期癌症患者中显示出剂量依赖性、非线性药代动力学。在1天内观察到骨转换标志物uNTx/Cr水平降低。降低的持续时间通常随剂量和给药频率增加。在患有实体瘤和骨转移的患者中，跨肿瘤类型和伴随癌症治疗（化疗和/或激素治疗）的药代动力学和药效学比较表明，肿瘤类型和伴随治疗类型均未显著影响地诺单抗的药代动力学或药效学。
地诺单抗在低于60mg的剂量下显示出非线性药代动力学，但在较高剂量下，在患有骨转移的晚期癌症患者中，地诺单抗的暴露量随剂量大致呈比例增加。按照每4周120mg的给药方案，在不同肿瘤类型中观察到相似的地诺单抗药代动力学和药效学，且与伴随癌症治疗无关。
