Pharmacokinetics (PK) and pharmacodynamics (PD) of AMG 162, a fully human monoclonal antibody to Receptor Activator of NF kappa B Ligand (RANKL), following a single subcutaneous dose to patients with cancer-related bone lesions.
Pharmacokinetics (PK) and pharmacodynamics (PD) of AMG 162, a fully human monoclonal antibody to Receptor Activator of NF kappa B Ligand (RANKL), following a single subcutaneous dose to patients with cancer-related bone lesions.
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AMG 162 是一种针对 NF kappa B 配体受体激活剂 (RANKL) 的全人单克隆抗体，对患有癌症相关骨病变的患者进行单次皮下注射后的药代动力学 (PK) 和药效学 (PD)。
DOI：
10.1200/jco.2004.22.90140.8106
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
P. Bekker
中科院分区：
文献类型：
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作者：
M. Peterson;Steven W. Martin;B. Stouch;D. Chen;D. Holloway;J. Body;A. Lipton;R. Coleman;P. Bekker
8106背景：RANKL是一种重要的骨细胞分化/活化因子。在乳腺癌（BC）或多发性骨髓瘤（MM）伴溶解性或混合性溶解性-母细胞性骨病变患者中进行的一项I期、单次给药、随机化、双盲、双模拟、活性对照（帕米膦酸盐）、剂量递增研究中评价了AMG 162的PK和PD。
方法
患者（n=54; 3-9/队列）接受AMG 162（0.1、0.3、1.0或3.0 mg/kg）或安慰剂（3：1比例）皮下（SC）注射和90 mg帕米膦酸盐或生理盐水静脉输注。采集血样和尿样，分别测定AMG 162血清浓度和骨吸收标志物N-端肽水平（uNTx/Cr）。
结果
在BC和MM患者中，AMG 162血清水平在给药后14 - 21天达到平均最大值448 ng/mL（0.1 mg/kg）至19，800 ng/mL（3.0 mg/kg），在给药后7 - 14天达到平均最大值625 ng/mL（0.1 mg/kg）至20，100 ng/mL（3.0 mg/kg）。BC和MM患者中，0.3 mg/kg剂量组的血清水平维持在100 ng/mL以上，3.0 mg/kg剂量组的血清水平维持在3000 ng/mL以上84天。BC和MM患者AMG 162给药后uNTx/Cr迅速降低（24小时内）。在0.3 mg/kg及以上剂量下，AMG 162对uNTx/Cr产生显著抑制，MM患者的中位最大抑制率大于50%，BC患者为75%。在研究期间（84天），1.0 mg/kg剂量在BC和MM患者中产生持续的中位抑制（>70%），而3.0 mg/kg剂量在BC中产生类似的抑制，但在MM患者中产生较小的抑制（> 38%）。
结论
AMG 162的有利PK和PD可能允许在骨病治疗中不频繁SC给药。[表：见正文]。
8106 Background: RANKL is an essential osteoclastic differentiation/activation factor. AMG 162 PK and PD were evaluated in a phase 1, single dose, randomized, double-blind, double-dummy, active control (pamidronate), dose escalation study, in patients with breast cancer (BC) or multiple myeloma (MM), with lytic or mixed lytic-blastic bone lesions.
METHODS
Patients (n=54; 3-9/cohort) received a subcutaneous (SC) injection of either AMG 162 (0.1, 0.3, 1.0, or 3.0 mg/kg) or placebo (3:1 ratio) and an intravenous infusion of either 90 mg of pamidronate or saline. Blood and urine samples were collected for determinations of AMG 162 serum concentrations and the bone resorption marker, N-telopeptide levels (uNTx/Cr), respectively.
RESULTS
AMG 162 serum levels reached average maximums of 448 ng/mL (0.1 mg/kg) to 19,800 ng/mL (3.0 mg/kg) 14 to 21 days post-dose, and 625 ng/mL (0.1 mg/kg) to 20,100 ng/mL (3.0 mg/kg) 7 to 14 days post-dose in BC and MM patients, respectively. Serum levels were maintained above 100 ng/mL at 0.3 mg/kg and above 3000 ng/mL for 84 days following 3.0 mg/kg in both BC and MM patients. Rapid decreases in uNTx/Cr (within 24 hours) followed AMG 162 administration in BC and MM patients. At 0.3 mg/kg and greater, AMG 162 produced marked suppression in uNTx/Cr with median maximal suppression of greater than 50% in MM and 75% in BC patients. A 1.0 mg/kg dose produced sustained median suppression (>70%) in BC and MM patients for the duration of the study (84 days), while a 3.0 mg/kg dose produced similar suppression in BC yet less suppression in MM patients (∼38%).
CONCLUSIONS
The favorable PK and PD of AMG 162 potentially allows for infrequent SC dosing in the treatment of bone disorders. [Table: see text].